REVIEW URRENT C OPINION
The perioperative management of patients maintained on medications used to manage opioid addiction Ethan O. Bryson a,b
Purpose of review The substantial increase in prescription and illicit opioid abuse observed over the last 2 decades has significantly increased the number of patients in recovery from addiction and now maintained on opioid replacement or agonist therapy. These patients present unique challenges to perioperative pain management. Recent findings Standard opioid-based analgesic techniques are often not sufficient when patients are maintained on medications used to manage opioid addiction. The current recommendations to support perioperative pain management plans in this population are based on a number of case reports and the shared experience of clinicians with success in treating these patients. Summary When possible, patients maintained on buprenorphine should be evaluated preoperatively to assess the feasibility of discontinuing the buprenorphine 72 h before surgery. If buprenorphine is continued during the perioperative period, patients may require significantly increased doses of standard opioids for analgesia. Patients maintained on methadone are at increased risk for respiratory-related complications and should receive a higher level of monitoring during the perioperative period. Patients who are on chronic methadone should continue their maintenance dose during the perioperative period. Where possible, nonopioid medications and regional anesthetic blockade are effective alternatives for analgesia in this population. Keywords buprenorphine, methadone, naloxone, naltrexone, slow-release oral morphine
INTRODUCTION As the number of persons addicted to illicit and prescription opioids continues to increase, so too does the number of persons in recovery from opioid addiction. Often these patients are maintained on medications used as part of a harm reduction strategy in order to avoid relapse and increase the odds that recovery will be successful. To this end, patients may be prescribed opioid agonists such as methadone or slow-release oral morphine (SROM), partial agonists such as buprenorphine, or antagonists such as naltrexone. Designed to prevent illicit opioids from producing euphoria, thus discouraging abuse, these medications have the unfortunate effect of interfering with the actions of opioids administered for legitimate medical indications. When these patients present for surgery or procedures requiring anesthesia, acute pain
management can become a significant challenge. In this review, the current evidence for effective pain management in this population is examined and the suggested strategies are outlined.
BUPRENORPHINE Buprenorphine is a semisynthetic opioid, a derivative of thebaine, first marketed by Reckitt and Colman in a
Department of Anesthesiology and bDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence to Ethan O. Bryson, MD, Department of Anesthesiology, Mount Sinai Hospital, One Gustave L Levy Place, New York, NY 10029, USA. Tel: +1 212 241 9240; fax: +1 212 876 3906; e-mail: [email protected] Curr Opin Anesthesiol 2014, 27:359–364 DOI:10.1097/ACO.0000000000000052
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KEY POINTS Because of buprenorphine’s unique pharmacology, patients maintained on this drug require substantially higher doses of opioids or alternative nonopioid-based techniques to achieve an adequate level of pain control in the perioperative setting. Ideally, buprenorphine should be discontinued 72 h before surgery, then restarted once the patient no longer has acute pain requiring narcotic analgesics. Methadone has a complex and variable pharmacology, and the potential for increased complications in patients maintained on this drug in the perioperative setting remains high. Patients on methadone maintenance should continue their usual daily dose up to and including the day of surgery. When patients maintained on medications used in the treatment of opioid addiction present for procedures or surgery requiring anesthesia, standard opioid-based analgesic techniques are often not sufficient and alternate analgesic agents should be considered.
the 1980s as an analgesic used to treat moderate pain. Soon after it was introduced, clinicians noticed that when buprenorphine was administered in higher dosages for moderate pain, patients received no relief from other opioids administered for breakthrough pain. This is because buprenorphine is a partial mu-receptor agonist and kappa-receptor antagonist with an extremely high affinity for these receptors. The affinity is so high, in fact, that it effectively blocks other opioids from binding to the mu-opioid and kappa-opioid receptors, preventing the patient from experiencing the effects of subsequently administered opioids [1]. This effect is similar to the effect of methadone used as opioid replacement therapy (ORT) in the harm reduction model of addiction treatment. Addicts maintained on these medications do not experience the euphoria from subsequently administered opioids – illicit or otherwise – effectively discouraging the opioid abuse. In 1995, buprenorphine was approved in France for use as a treatment for opioid dependence and is currently approved for such use in 44 countries [2 ]. Buprenorphine is manufactured for this indication in 2 and 8 mg formulations, and marketed as a buprenorphine-only product (Subutex, Reckitt Benckiser, Bristol, UK) and as a buprenorphine and naloxone combination product (Suboxone, Reckitt Benckiser). In the combination product, the naloxone is not absorbed to any appreciable degree when taken as directed (sublingually), but is included in the formulation to discourage &
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intravenous use. Compared with full mu-agonists such as methadone, buprenorphine has a slower dissociation time which allows for less frequent dosing and is associated with less respiratory depression, making it a somewhat safer medication. Unfortunately, this slow dissociation from mu-receptors can make detoxification difficult and has the potential to significantly complicate the perioperative management of patients maintained on this drug. To date, there have been no randomized controlled studies published involving the effects of different pain control modalities applied to patients maintained on buprenorphine. Evidence supporting the recommendations for the management of these patients is currently based on a number of case reports and the shared experience of clinicians with success in treating this patient group. Historical recommendations proposed for the control of acute pain in the patient maintained on buprenorphine have included the use of higher doses of short-acting opioid analgesics in addition to the maintenance dose of buprenorphine; relying solely on the analgesic properties of buprenorphine itself by increasing the total daily dose; replacing buprenorphine with methadone and adding short-acting opioid analgesic for breakthrough pain; or replacing buprenorphine with another opioid analgesic altogether (see list below) [3]. Some of these recommendations have subsequently been shown to be more effective than others. The use of short-acting opioid agonists to control acute pain in the patient maintained on buprenorphine typically requires doses considerably higher than most practitioners routinely administer. McCormick et al. [4 ] reported the difficulties associated with the management of acute pain from compartment syndrome in a 50-year-old man with McArdle’s disease who was maintained on buprenorphine and naloxone for chronic pain and opioid dependence. Their successful management of this case involved stopping the buprenorphine and naloxone, and administering escalating doses of hydromorphone until pain relief was achieved. Twelve milligrams of intravenous hydromorphone had little effect on the patient’s initial pain scores, and his pain was not effectively controlled (reduced to 3 out of 10) until 48 h after admission. At that time, the patient had already undergone surgery and was receiving hydromorphone via patient-controlled analgesia (PCA) with 0.8 mg (15 min lockout) on top of a 0.5-mg/h basal rate. Elevated doses of hydromorphone, even in opioid-tolerant patients, can significantly increase the risk for overdose and respiratory depression. As the effects of buprenorphine can last for at least 24–72 h once the drug is discontinued &
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and because the pharmacology is highly variable, it is important to manage these patients in a setting with increased vigilance and apnea monitoring. McCormick et al. recommend this type of monitoring be continued for at least the first 72 h after the last dose of buprenorphine. In a retrospective cohort study, MacIntyre et al. [5 ] describe their experience with pain relief and opioid requirements in the first 24 h after surgery in patients maintained on either buprenorphine (n ¼ 22) or methadone (n ¼ 26) who received postoperative analgesia via PCA. The authors report no significant differences in pain scores or side-effects between the two patient groups, or between those patients within each group who had or had not received their methadone or buprenorphine the day after surgery. They did, however, report a statistically significant increase in PCA use in patients who had not received their daily buprenorphine. According to the authors, these results suggest that continuation of buprenorphine during the perioperative period is appropriate. This is in contrast to the routine practice of discontinuing buprenorphine prior to surgery and suggests that management of the patient maintained on buprenorphine, though complicated by its unique pharmacology, is possible and may be worth the extra effort. The successful use of increased doses of buprenorphine used as the sole analgesic agent for perioperative pain control has been reported [6], but the ceiling effect of this drug (above 32 mg/day sublingual) limits this application to situations in which pain is expected to be only mild to moderate. If buprenorphine is to be used as the sole analgesic agent, the total daily dose should be administered in divided doses every 6–8 h [7 ]. In cases in which moderate-to-severe pain is expected, a drug holiday or transition from buprenorphine to methadone maintenance allows for more effective perioperative pain control, as methadone does not have a ceiling effect (see list below). Many patients, however, are hesitant to discontinue ORT altogether for fear of relapse, and transitioning back to buprenorphine from methadone can be problematic. It is becoming clear that for patients on ORT, as for many patients, perhaps the most effective approach to pain management involves the use of multimodal analgesia, including the use of regional anesthesia whenever possible. Israel and Poore [8 ] report the effective management of a 37-year-old woman status postbilateral mastectomies who was maintained on buprenorphine–naloxone for opioid dependence. In this case, the patient’s buprenorphine was discontinued 72 h prior to surgery and replaced with a fentanyl patch. Postoperatively, a fentanyl PCA and ketorolac (15 mg every 6 h) were &
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added, but her pain could not be controlled. Effective pain management was subsequently achieved by replacing the fentanyl PCA with 10–30 mg of oxycodone every 3 h and 1000 mg acetaminophen every 8 h while leaving the fentanyl patch in place. Following control of her acute pain, the patient was discharged with a plan in place to taper her pain medications as an outpatient [9]. When faced with the patient maintained on high-dose buprenorphine, avoiding opioid analgesia altogether is ideal, if feasible. Gilmore et al. [10] report a case involving a 22-year-old man maintained on buprenorphine for opioid dependence who presented to the emergency department after a workrelated injury. The man had sustained a severe wrist fracture and was in significant pain but received no relief despite 10 mg of morphine administered subcutaneously, a bolus of remifentanil (1 mg/kg) and an infusion of remifentanil (1.7 mg/kg/min). A bier block provided complete analgesia within 5 min of placement. When regional anesthesia is practical, a catheter should be placed whenever possible, so that postoperative analgesia can be maintained once the initial nerve block has worn off. The use of nonopioid medications for pain control in the patient maintained on buprenorphine was recently reviewed by Wasson and Beirne [11 ]. Ketamine exerts its effects primarily as an antagonist at the N-methyl-D-aspartate receptor, so there is little interference from buprenorphine, and infusions of this drug may be combined with other drugs as part of a multimodal approach. Though there are no recent publications describing the experience with this drug in the opioid-dependent population, ketamine has been shown to be opioid sparing when used in the perioperative setting [12]. It is, therefore, reasonable to assume that the addition of a lowdose (0.1 mg/kg/h) ketamine infusion as part of a multimodal approach to pain management may be helpful in this population. On the basis of collective experience and currently available evidence, the preferred approach to the management of patients on buprenorphine maintenance is to stop buprenorphine therapy before surgery. Ideally, discontinuation of buprenorphine prior to surgery is accomplished via a gradual reduction of the patient’s maintenance dose over a period of 2 weeks, in which dosage is decreased by 2 mg every 2–3 days and completely discontinued 3 days before surgery. If time does not permit, discontinuation can take place over a period as short as 3 days, though the risk for withdrawal symptoms and subsequent relapse with this approach is higher. If patients are unable to tolerate abrupt discontinuation, the maintenance dose of buprenorphine should be replaced with methadone
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or another opioid before surgery. The first list below summarizes the effective perioperative management strategies for patients maintained on buprenorphine and the second list below describes the perioperative transition from buprenorphine to methadone. Perioperative management strategies for patients maintained on buprenorphine are as follows (In either case, use nonopioid medications and employ regional anesthetic blockade where possible.): (1) If the plan is to continue the buprenorphine: (a) Use short-acting opioid analgesics such as fentanyl in addition to the once-daily maintenance dose of buprenorphine and titrate to achieve effective pain control. (Note: effective doses may be much higher.) (b) Instead of once-daily dosing, divide the total buprenorphine maintenance dose over the course of 24 h and administer every 6–8 h (relying solely on the analgesic properties of buprenorphine is only effective for mild-to-moderate pain). (2) If the plan is to stop the buprenorphine: (a) Stop the buprenorphine 72 h before surgery and use standard opioids for analgesia. (b) Conduct a slow taper over 2 weeks or an abrupt taper over 3 days followed by 72 h completely free of buprenorphine prior to elective surgery. (c) If the risk for relapse is too high, replace the maintenance dose of buprenorphine with methadone before surgery and then use another short-acting opioid analgesic for breakthrough pain. Perioperative transition from buprenorphine to methadone is as follows: (1) Patients maintained on buprenorphine should receive 30–40 mg methadone per day. (2) This dose of methadone will prevent acute withdrawal in most patients. (3) For persistent opioid withdrawal, increase daily methadone by 5–10 mg each day. (4) When the acute pain resolves, discontinue methadone and resume ORT with buprenorphine using an induction protocol (patient should be in mild opioid withdrawal before restarting buprenorphine therapy to avoid precipitation of acute withdrawal).
METHADONE Methadone was first synthesized during World War II because of a shortage of morphine and introduced in 1947 as an analgesic. Unlike buprenorphine, it is 362
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a full agonist that binds to and activates opioid receptors in the same way that commonly abused opioids such as heroin do. Unlike heroin, however, methadone has a long half-life (its effects may last up to 24 h) and is associated with less euphoria and other opioid-like effects, therefore making it less likely to be abused by addicts attempting to get ‘high’. In higher doses, methadone effectively prevents the patient from experiencing the euphoria and other effects of subsequently administered opioid medications, and helps patients avoid opioid withdrawal symptoms. With the introduction of buprenorphine into clinical use as ORT, the number of patients maintained on methadone has decreased as a percentage of total patients on ORT, but the number of addicts maintained on this drug is still substantially greater than those maintained on buprenorphine. As well, more and more patients are receiving methadone for the treatment of chronic pain conditions. Patients in formal methadone maintenance programs as well as those prescribed methadone for chronic pain present specific challenges in the perioperative setting. In addition to having opioid tolerance, these patients may also have developed hyperalgesia or pain intolerance because of the upregulation of pronociceptive systems. In addition, the pharmacology of methadone is highly variable and there is a strong potential for interaction between methadone and other medications, further complicating the management of these patients. Methadone has also been associated with life-threatening arrhythmias and QT prolongation. Therefore, drugs which may further prolong the QT interval should be administered with care and with appropriate ECG monitoring. Patients maintained on methadone should be encouraged to continue their maintenance dose during the perioperative period, and additional opioids should be used during surgery or for breakthrough pain in the postoperative period. It should be expected that the total dose of supplemental opioids required to achieve adequate pain control in these patients will far exceed the expected dose for opioid-naı¨ve patients. As a result, postoperative monitoring for respiratory depression is essential.
NALTREXONE Patients in recovery from addiction to opioid medications, and in some cases to alcohol, may present for surgery while maintained on naltrexone. This drug is available in an oral form (ReVia, Barr Pharmaceuticals, Inc., Pomona, New York, USA; Depade, Mallinckrodt, Inc., St. Louis, Missouri, USA), which must be taken daily, or in an Volume 27 Number 3 June 2014
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Medications used to manage opioid addiction Bryson
extended-release form (XR-NTX, Vivitrol, Alkermes, Waltham, Massachusetts, USA), which is administered through monthly depot injections. Several different formulations of sustained-release naltrexone products, which are implanted under the skin require less frequent administration, are currently in development or available in other countries. Naltrexone is a competitive opioid receptor antagonist that prevents the patient from experiencing the euphoric effects of opioid drugs. The plasma half-life of naltrexone is 4 h, and the half-life of the active metabolite, 6-b-naltrexol, is 13 h. The extended-release formulation maintains clinically significant plasma levels for a period of roughly 30 days [13]. In addition to opioid antagonism, naltrexone has also been shown to reduce cravings for opioid drugs as well as for alcohol. For this reason, it is being prescribed increasingly for patients with difficult to control disease or those who must return to work in high-risk settings (such as healthcare professionals). Israel and Poore [8 ] recently described the perioperative management of a 27-year-old man status postmastectomy for gynecomastia who was maintained on intramuscular extended-release naltrexone for opioid dependence. There is some evidence that patients who are chronically maintained on this drug may experience an upregulation of their opioid receptors, resulting in an exaggerated response to opioid agonists administered for the treatment of acute pain [14]. In this case, the naltrexone was stopped prior to surgery (though it is not indicated for how long), and the authors were able to successfully manage this patient’s postoperative pain with 50–100 mg of tramadol every 6 h. If a greater degree of analgesia is required, the competitive blockade of naltrexone can be overcome with opioid agonists, but the required doses are on the order of 10–20 times the usual doses by weight [15]. Because the extended-release formulation of this drug is dosed on a once-per-month basis, elective surgeries should be scheduled no sooner than 30 days after the last naltrexone injection. During the perioperative period, patients are at increased risk for relapse and the decision to delay naltrexone redosing until after the acute perioperative period should be made in conjunction with the treating addictionologist.
opioid-dependent persons. Originally developed for pain relief and used interchangeably with methadone in this setting, SROM is marketed for use in ORT as capsules which contain morphine sulfate with a slow-release coating. These capsules – which are taken orally – release the drug over a 24-h period, allowing for once-daily dosing similar to methadone [16 ]. As with methadone and buprenorphine, patients maintained on SROM are able to avoid the withdrawal symptoms and abstain from illicit opioid use, but unlike other medications used for ORT, opioid receptors are not blocked and subsequent opioid administration will still have an effect. Because experience with the use of SROM for ORT is limited, and because there is insufficient evidence to support widespread use, this drug will likely be encountered infrequently in the perioperative setting. Patients who present having taken SROM for opioid dependence may be treated the same as any opioid-tolerant patient, as this particular formulation of morphine has no unique effect.
SLOW-RELEASE ORAL MORPHINE
1. Gevirtz C, Frost EA, Bryson EO. Perioperative implications of buprenorphine maintenance treatment for opioid addiction. Int Anesthesiol Clin 2011; 49:147–155. 2. Hamza H, Bryson EO. Buprenorphine maintenance therapy in the opioid & addicted Healthcare Professional returning to clinical practice – a hidden controversy. Mayo Clin Proc 2012; 87:260–267. This study demonstrates the degree to which the use of buprenorphine has expanded since its introduction into the opioid replacement market.
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As some people respond poorly to buprenorphine or methadone, either because of intolerable sideeffects or because of inadequate withdrawal suppression, SROM is sometimes used for maintenance in
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CONCLUSION Buprenorphine, either alone or in combination with naloxone, methadone, naltrexone, and SROM are prescribed for opioid maintenance therapy in patients recovering from opioid addiction. When patients maintained on any of these agents present for procedures or surgery requiring anesthesia, standard opioid-based analgesic techniques are often not sufficient to achieve adequate pain control. The anesthesiologist must be aware of this need and be prepared to adjust the anesthetic and pain management plans accordingly. Acknowledgements Support statement: Support was provided solely from the institutional and departmental sources. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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Anesthesia and medical disease 3. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006; 144:127–134. 4. McCormick Z, Chu SK, Chang-Chien GC, Joseph P. Acute pain control & challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle’s disease: a case report and review. Pain Med 2013; 14:1187–1191. This study highlights the issue of increased risk for respiratory depression in patients who receive elevated doses of opioids, even in opioid-tolerant patients. 5. MacIntyre PE, Russell RA, Usher KA, et al. Pain relief and opioid & requirements in the first 24 h after surgery in patients taking buprenorphine and methadone opioid substitution therapy. Anaesth Intensive Care 2013; 41:222–230. Though a retrospective study, the authors suggest that continuation of buprenorphine during the perioperative is appropriate. 6. Book S, Myrick H, Malcom R, et al. Buprenorphine for postoperative pain following general surgery in a buprenorphine maintained patient. Am J Psychiatry 2007; 164:979. 7. Childers JW, Arnold RM. Treatment of pain in patients taking buprenorphine & for opioid addiction. J Palliat Med 2012; 15:613–614. These authors suggest that if buprenorphine is to be used as the sole analgesic agent, the total daily dose should be administered in divided doses every 6–8 h. 8. Israel JS, Poore SO. The clinical conundrum of perioperative pain manage& ment in patients with opioid dependence: lessons from two cases. Plast Reconstr Surg 2013; 131:657e–658e. These authors present a more effective approach to perioperative pain management in this population involving the use of multimodal analgesia, including regional anesthesia.
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9. Huxtable CA, Roberts LJ, Somogy AA, MacIntyre PE. Acute pain management in opioid-tolerant patients: a growing challenge. Anesthesia Intensive Care 2011; 39:804–823. 10. Gilmore T, Saccheti A, Cortese T. Buprenorphine/naloxone inhibition of remifentanil procedural sedation. Am J Emerg Med 2012; 30:1655e3–1655e4. 11. Wasson M, Beirne OR. Buprenorphine therapy: an increasing challenge in oral & and maxillofacial surgery. Med Manag Pharmacol Update 2013; 116:142–146. The use of nonopioid medications for pain control in the patient maintained on buprenorphine is reviewed in this study. 12. Zakine J, Samarcq D, Lorne E, et al. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg 2008; 106:1856– 1861. 13. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo controlled, multicenter randomized trial. Lancet 2011; 377:1506–1513. 14. Vickers AP, Jolly A. Naltrexone and problems in pain management. Br Med J 2006; 332:132–133. 15. Dean RL, Todtenkopf MS, Deaver DR, et al. Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone. Pharmacol Biochem Behav 2008; 89:515–522. 16. Bond AJ, Reed KDF, Beavan P, Strang J. After the randomized injectable & opiate treatment trial: posttrial investigation of slow-release oral morphine as an alternative to opiate maintenance medication. Drug Alcohol Rev 2013; 31:492–498. Patients who present having taken SROM for opioid dependence may be treated the same as any opioid-tolerant patient, as this particular formulation of morphine has no unique effects.
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The perioperative management of patients maintained on medications used to manage opioid addiction Ethan O. Bryson a,b
Purpose of review The substantial increase in prescription and illicit opioid abuse observed over the last 2 decades has significantly increased the number of patients in recovery from addiction and now maintained on opioid replacement or agonist therapy. These patients present unique challenges to perioperative pain management. Recent findings Standard opioid-based analgesic techniques are often not sufficient when patients are maintained on medications used to manage opioid addiction. The current recommendations to support perioperative pain management plans in this population are based on a number of case reports and the shared experience of clinicians with success in treating these patients. Summary When possible, patients maintained on buprenorphine should be evaluated preoperatively to assess the feasibility of discontinuing the buprenorphine 72 h before surgery. If buprenorphine is continued during the perioperative period, patients may require significantly increased doses of standard opioids for analgesia. Patients maintained on methadone are at increased risk for respiratory-related complications and should receive a higher level of monitoring during the perioperative period. Patients who are on chronic methadone should continue their maintenance dose during the perioperative period. Where possible, nonopioid medications and regional anesthetic blockade are effective alternatives for analgesia in this population. Keywords buprenorphine, methadone, naloxone, naltrexone, slow-release oral morphine
INTRODUCTION As the number of persons addicted to illicit and prescription opioids continues to increase, so too does the number of persons in recovery from opioid addiction. Often these patients are maintained on medications used as part of a harm reduction strategy in order to avoid relapse and increase the odds that recovery will be successful. To this end, patients may be prescribed opioid agonists such as methadone or slow-release oral morphine (SROM), partial agonists such as buprenorphine, or antagonists such as naltrexone. Designed to prevent illicit opioids from producing euphoria, thus discouraging abuse, these medications have the unfortunate effect of interfering with the actions of opioids administered for legitimate medical indications. When these patients present for surgery or procedures requiring anesthesia, acute pain
management can become a significant challenge. In this review, the current evidence for effective pain management in this population is examined and the suggested strategies are outlined.
BUPRENORPHINE Buprenorphine is a semisynthetic opioid, a derivative of thebaine, first marketed by Reckitt and Colman in a
Department of Anesthesiology and bDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence to Ethan O. Bryson, MD, Department of Anesthesiology, Mount Sinai Hospital, One Gustave L Levy Place, New York, NY 10029, USA. Tel: +1 212 241 9240; fax: +1 212 876 3906; e-mail: [email protected] Curr Opin Anesthesiol 2014, 27:359–364 DOI:10.1097/ACO.0000000000000052
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KEY POINTS Because of buprenorphine’s unique pharmacology, patients maintained on this drug require substantially higher doses of opioids or alternative nonopioid-based techniques to achieve an adequate level of pain control in the perioperative setting. Ideally, buprenorphine should be discontinued 72 h before surgery, then restarted once the patient no longer has acute pain requiring narcotic analgesics. Methadone has a complex and variable pharmacology, and the potential for increased complications in patients maintained on this drug in the perioperative setting remains high. Patients on methadone maintenance should continue their usual daily dose up to and including the day of surgery. When patients maintained on medications used in the treatment of opioid addiction present for procedures or surgery requiring anesthesia, standard opioid-based analgesic techniques are often not sufficient and alternate analgesic agents should be considered.
the 1980s as an analgesic used to treat moderate pain. Soon after it was introduced, clinicians noticed that when buprenorphine was administered in higher dosages for moderate pain, patients received no relief from other opioids administered for breakthrough pain. This is because buprenorphine is a partial mu-receptor agonist and kappa-receptor antagonist with an extremely high affinity for these receptors. The affinity is so high, in fact, that it effectively blocks other opioids from binding to the mu-opioid and kappa-opioid receptors, preventing the patient from experiencing the effects of subsequently administered opioids [1]. This effect is similar to the effect of methadone used as opioid replacement therapy (ORT) in the harm reduction model of addiction treatment. Addicts maintained on these medications do not experience the euphoria from subsequently administered opioids – illicit or otherwise – effectively discouraging the opioid abuse. In 1995, buprenorphine was approved in France for use as a treatment for opioid dependence and is currently approved for such use in 44 countries [2 ]. Buprenorphine is manufactured for this indication in 2 and 8 mg formulations, and marketed as a buprenorphine-only product (Subutex, Reckitt Benckiser, Bristol, UK) and as a buprenorphine and naloxone combination product (Suboxone, Reckitt Benckiser). In the combination product, the naloxone is not absorbed to any appreciable degree when taken as directed (sublingually), but is included in the formulation to discourage &
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intravenous use. Compared with full mu-agonists such as methadone, buprenorphine has a slower dissociation time which allows for less frequent dosing and is associated with less respiratory depression, making it a somewhat safer medication. Unfortunately, this slow dissociation from mu-receptors can make detoxification difficult and has the potential to significantly complicate the perioperative management of patients maintained on this drug. To date, there have been no randomized controlled studies published involving the effects of different pain control modalities applied to patients maintained on buprenorphine. Evidence supporting the recommendations for the management of these patients is currently based on a number of case reports and the shared experience of clinicians with success in treating this patient group. Historical recommendations proposed for the control of acute pain in the patient maintained on buprenorphine have included the use of higher doses of short-acting opioid analgesics in addition to the maintenance dose of buprenorphine; relying solely on the analgesic properties of buprenorphine itself by increasing the total daily dose; replacing buprenorphine with methadone and adding short-acting opioid analgesic for breakthrough pain; or replacing buprenorphine with another opioid analgesic altogether (see list below) [3]. Some of these recommendations have subsequently been shown to be more effective than others. The use of short-acting opioid agonists to control acute pain in the patient maintained on buprenorphine typically requires doses considerably higher than most practitioners routinely administer. McCormick et al. [4 ] reported the difficulties associated with the management of acute pain from compartment syndrome in a 50-year-old man with McArdle’s disease who was maintained on buprenorphine and naloxone for chronic pain and opioid dependence. Their successful management of this case involved stopping the buprenorphine and naloxone, and administering escalating doses of hydromorphone until pain relief was achieved. Twelve milligrams of intravenous hydromorphone had little effect on the patient’s initial pain scores, and his pain was not effectively controlled (reduced to 3 out of 10) until 48 h after admission. At that time, the patient had already undergone surgery and was receiving hydromorphone via patient-controlled analgesia (PCA) with 0.8 mg (15 min lockout) on top of a 0.5-mg/h basal rate. Elevated doses of hydromorphone, even in opioid-tolerant patients, can significantly increase the risk for overdose and respiratory depression. As the effects of buprenorphine can last for at least 24–72 h once the drug is discontinued &
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and because the pharmacology is highly variable, it is important to manage these patients in a setting with increased vigilance and apnea monitoring. McCormick et al. recommend this type of monitoring be continued for at least the first 72 h after the last dose of buprenorphine. In a retrospective cohort study, MacIntyre et al. [5 ] describe their experience with pain relief and opioid requirements in the first 24 h after surgery in patients maintained on either buprenorphine (n ¼ 22) or methadone (n ¼ 26) who received postoperative analgesia via PCA. The authors report no significant differences in pain scores or side-effects between the two patient groups, or between those patients within each group who had or had not received their methadone or buprenorphine the day after surgery. They did, however, report a statistically significant increase in PCA use in patients who had not received their daily buprenorphine. According to the authors, these results suggest that continuation of buprenorphine during the perioperative period is appropriate. This is in contrast to the routine practice of discontinuing buprenorphine prior to surgery and suggests that management of the patient maintained on buprenorphine, though complicated by its unique pharmacology, is possible and may be worth the extra effort. The successful use of increased doses of buprenorphine used as the sole analgesic agent for perioperative pain control has been reported [6], but the ceiling effect of this drug (above 32 mg/day sublingual) limits this application to situations in which pain is expected to be only mild to moderate. If buprenorphine is to be used as the sole analgesic agent, the total daily dose should be administered in divided doses every 6–8 h [7 ]. In cases in which moderate-to-severe pain is expected, a drug holiday or transition from buprenorphine to methadone maintenance allows for more effective perioperative pain control, as methadone does not have a ceiling effect (see list below). Many patients, however, are hesitant to discontinue ORT altogether for fear of relapse, and transitioning back to buprenorphine from methadone can be problematic. It is becoming clear that for patients on ORT, as for many patients, perhaps the most effective approach to pain management involves the use of multimodal analgesia, including the use of regional anesthesia whenever possible. Israel and Poore [8 ] report the effective management of a 37-year-old woman status postbilateral mastectomies who was maintained on buprenorphine–naloxone for opioid dependence. In this case, the patient’s buprenorphine was discontinued 72 h prior to surgery and replaced with a fentanyl patch. Postoperatively, a fentanyl PCA and ketorolac (15 mg every 6 h) were &
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added, but her pain could not be controlled. Effective pain management was subsequently achieved by replacing the fentanyl PCA with 10–30 mg of oxycodone every 3 h and 1000 mg acetaminophen every 8 h while leaving the fentanyl patch in place. Following control of her acute pain, the patient was discharged with a plan in place to taper her pain medications as an outpatient [9]. When faced with the patient maintained on high-dose buprenorphine, avoiding opioid analgesia altogether is ideal, if feasible. Gilmore et al. [10] report a case involving a 22-year-old man maintained on buprenorphine for opioid dependence who presented to the emergency department after a workrelated injury. The man had sustained a severe wrist fracture and was in significant pain but received no relief despite 10 mg of morphine administered subcutaneously, a bolus of remifentanil (1 mg/kg) and an infusion of remifentanil (1.7 mg/kg/min). A bier block provided complete analgesia within 5 min of placement. When regional anesthesia is practical, a catheter should be placed whenever possible, so that postoperative analgesia can be maintained once the initial nerve block has worn off. The use of nonopioid medications for pain control in the patient maintained on buprenorphine was recently reviewed by Wasson and Beirne [11 ]. Ketamine exerts its effects primarily as an antagonist at the N-methyl-D-aspartate receptor, so there is little interference from buprenorphine, and infusions of this drug may be combined with other drugs as part of a multimodal approach. Though there are no recent publications describing the experience with this drug in the opioid-dependent population, ketamine has been shown to be opioid sparing when used in the perioperative setting [12]. It is, therefore, reasonable to assume that the addition of a lowdose (0.1 mg/kg/h) ketamine infusion as part of a multimodal approach to pain management may be helpful in this population. On the basis of collective experience and currently available evidence, the preferred approach to the management of patients on buprenorphine maintenance is to stop buprenorphine therapy before surgery. Ideally, discontinuation of buprenorphine prior to surgery is accomplished via a gradual reduction of the patient’s maintenance dose over a period of 2 weeks, in which dosage is decreased by 2 mg every 2–3 days and completely discontinued 3 days before surgery. If time does not permit, discontinuation can take place over a period as short as 3 days, though the risk for withdrawal symptoms and subsequent relapse with this approach is higher. If patients are unable to tolerate abrupt discontinuation, the maintenance dose of buprenorphine should be replaced with methadone
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or another opioid before surgery. The first list below summarizes the effective perioperative management strategies for patients maintained on buprenorphine and the second list below describes the perioperative transition from buprenorphine to methadone. Perioperative management strategies for patients maintained on buprenorphine are as follows (In either case, use nonopioid medications and employ regional anesthetic blockade where possible.): (1) If the plan is to continue the buprenorphine: (a) Use short-acting opioid analgesics such as fentanyl in addition to the once-daily maintenance dose of buprenorphine and titrate to achieve effective pain control. (Note: effective doses may be much higher.) (b) Instead of once-daily dosing, divide the total buprenorphine maintenance dose over the course of 24 h and administer every 6–8 h (relying solely on the analgesic properties of buprenorphine is only effective for mild-to-moderate pain). (2) If the plan is to stop the buprenorphine: (a) Stop the buprenorphine 72 h before surgery and use standard opioids for analgesia. (b) Conduct a slow taper over 2 weeks or an abrupt taper over 3 days followed by 72 h completely free of buprenorphine prior to elective surgery. (c) If the risk for relapse is too high, replace the maintenance dose of buprenorphine with methadone before surgery and then use another short-acting opioid analgesic for breakthrough pain. Perioperative transition from buprenorphine to methadone is as follows: (1) Patients maintained on buprenorphine should receive 30–40 mg methadone per day. (2) This dose of methadone will prevent acute withdrawal in most patients. (3) For persistent opioid withdrawal, increase daily methadone by 5–10 mg each day. (4) When the acute pain resolves, discontinue methadone and resume ORT with buprenorphine using an induction protocol (patient should be in mild opioid withdrawal before restarting buprenorphine therapy to avoid precipitation of acute withdrawal).
METHADONE Methadone was first synthesized during World War II because of a shortage of morphine and introduced in 1947 as an analgesic. Unlike buprenorphine, it is 362
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a full agonist that binds to and activates opioid receptors in the same way that commonly abused opioids such as heroin do. Unlike heroin, however, methadone has a long half-life (its effects may last up to 24 h) and is associated with less euphoria and other opioid-like effects, therefore making it less likely to be abused by addicts attempting to get ‘high’. In higher doses, methadone effectively prevents the patient from experiencing the euphoria and other effects of subsequently administered opioid medications, and helps patients avoid opioid withdrawal symptoms. With the introduction of buprenorphine into clinical use as ORT, the number of patients maintained on methadone has decreased as a percentage of total patients on ORT, but the number of addicts maintained on this drug is still substantially greater than those maintained on buprenorphine. As well, more and more patients are receiving methadone for the treatment of chronic pain conditions. Patients in formal methadone maintenance programs as well as those prescribed methadone for chronic pain present specific challenges in the perioperative setting. In addition to having opioid tolerance, these patients may also have developed hyperalgesia or pain intolerance because of the upregulation of pronociceptive systems. In addition, the pharmacology of methadone is highly variable and there is a strong potential for interaction between methadone and other medications, further complicating the management of these patients. Methadone has also been associated with life-threatening arrhythmias and QT prolongation. Therefore, drugs which may further prolong the QT interval should be administered with care and with appropriate ECG monitoring. Patients maintained on methadone should be encouraged to continue their maintenance dose during the perioperative period, and additional opioids should be used during surgery or for breakthrough pain in the postoperative period. It should be expected that the total dose of supplemental opioids required to achieve adequate pain control in these patients will far exceed the expected dose for opioid-naı¨ve patients. As a result, postoperative monitoring for respiratory depression is essential.
NALTREXONE Patients in recovery from addiction to opioid medications, and in some cases to alcohol, may present for surgery while maintained on naltrexone. This drug is available in an oral form (ReVia, Barr Pharmaceuticals, Inc., Pomona, New York, USA; Depade, Mallinckrodt, Inc., St. Louis, Missouri, USA), which must be taken daily, or in an Volume 27 Number 3 June 2014
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Medications used to manage opioid addiction Bryson
extended-release form (XR-NTX, Vivitrol, Alkermes, Waltham, Massachusetts, USA), which is administered through monthly depot injections. Several different formulations of sustained-release naltrexone products, which are implanted under the skin require less frequent administration, are currently in development or available in other countries. Naltrexone is a competitive opioid receptor antagonist that prevents the patient from experiencing the euphoric effects of opioid drugs. The plasma half-life of naltrexone is 4 h, and the half-life of the active metabolite, 6-b-naltrexol, is 13 h. The extended-release formulation maintains clinically significant plasma levels for a period of roughly 30 days [13]. In addition to opioid antagonism, naltrexone has also been shown to reduce cravings for opioid drugs as well as for alcohol. For this reason, it is being prescribed increasingly for patients with difficult to control disease or those who must return to work in high-risk settings (such as healthcare professionals). Israel and Poore [8 ] recently described the perioperative management of a 27-year-old man status postmastectomy for gynecomastia who was maintained on intramuscular extended-release naltrexone for opioid dependence. There is some evidence that patients who are chronically maintained on this drug may experience an upregulation of their opioid receptors, resulting in an exaggerated response to opioid agonists administered for the treatment of acute pain [14]. In this case, the naltrexone was stopped prior to surgery (though it is not indicated for how long), and the authors were able to successfully manage this patient’s postoperative pain with 50–100 mg of tramadol every 6 h. If a greater degree of analgesia is required, the competitive blockade of naltrexone can be overcome with opioid agonists, but the required doses are on the order of 10–20 times the usual doses by weight [15]. Because the extended-release formulation of this drug is dosed on a once-per-month basis, elective surgeries should be scheduled no sooner than 30 days after the last naltrexone injection. During the perioperative period, patients are at increased risk for relapse and the decision to delay naltrexone redosing until after the acute perioperative period should be made in conjunction with the treating addictionologist.
opioid-dependent persons. Originally developed for pain relief and used interchangeably with methadone in this setting, SROM is marketed for use in ORT as capsules which contain morphine sulfate with a slow-release coating. These capsules – which are taken orally – release the drug over a 24-h period, allowing for once-daily dosing similar to methadone [16 ]. As with methadone and buprenorphine, patients maintained on SROM are able to avoid the withdrawal symptoms and abstain from illicit opioid use, but unlike other medications used for ORT, opioid receptors are not blocked and subsequent opioid administration will still have an effect. Because experience with the use of SROM for ORT is limited, and because there is insufficient evidence to support widespread use, this drug will likely be encountered infrequently in the perioperative setting. Patients who present having taken SROM for opioid dependence may be treated the same as any opioid-tolerant patient, as this particular formulation of morphine has no unique effect.
SLOW-RELEASE ORAL MORPHINE
1. Gevirtz C, Frost EA, Bryson EO. Perioperative implications of buprenorphine maintenance treatment for opioid addiction. Int Anesthesiol Clin 2011; 49:147–155. 2. Hamza H, Bryson EO. Buprenorphine maintenance therapy in the opioid & addicted Healthcare Professional returning to clinical practice – a hidden controversy. Mayo Clin Proc 2012; 87:260–267. This study demonstrates the degree to which the use of buprenorphine has expanded since its introduction into the opioid replacement market.
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As some people respond poorly to buprenorphine or methadone, either because of intolerable sideeffects or because of inadequate withdrawal suppression, SROM is sometimes used for maintenance in
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CONCLUSION Buprenorphine, either alone or in combination with naloxone, methadone, naltrexone, and SROM are prescribed for opioid maintenance therapy in patients recovering from opioid addiction. When patients maintained on any of these agents present for procedures or surgery requiring anesthesia, standard opioid-based analgesic techniques are often not sufficient to achieve adequate pain control. The anesthesiologist must be aware of this need and be prepared to adjust the anesthetic and pain management plans accordingly. Acknowledgements Support statement: Support was provided solely from the institutional and departmental sources. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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Anesthesia and medical disease 3. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006; 144:127–134. 4. McCormick Z, Chu SK, Chang-Chien GC, Joseph P. Acute pain control & challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle’s disease: a case report and review. Pain Med 2013; 14:1187–1191. This study highlights the issue of increased risk for respiratory depression in patients who receive elevated doses of opioids, even in opioid-tolerant patients. 5. MacIntyre PE, Russell RA, Usher KA, et al. Pain relief and opioid & requirements in the first 24 h after surgery in patients taking buprenorphine and methadone opioid substitution therapy. Anaesth Intensive Care 2013; 41:222–230. Though a retrospective study, the authors suggest that continuation of buprenorphine during the perioperative is appropriate. 6. Book S, Myrick H, Malcom R, et al. Buprenorphine for postoperative pain following general surgery in a buprenorphine maintained patient. Am J Psychiatry 2007; 164:979. 7. Childers JW, Arnold RM. Treatment of pain in patients taking buprenorphine & for opioid addiction. J Palliat Med 2012; 15:613–614. These authors suggest that if buprenorphine is to be used as the sole analgesic agent, the total daily dose should be administered in divided doses every 6–8 h. 8. Israel JS, Poore SO. The clinical conundrum of perioperative pain manage& ment in patients with opioid dependence: lessons from two cases. Plast Reconstr Surg 2013; 131:657e–658e. These authors present a more effective approach to perioperative pain management in this population involving the use of multimodal analgesia, including regional anesthesia.
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9. Huxtable CA, Roberts LJ, Somogy AA, MacIntyre PE. Acute pain management in opioid-tolerant patients: a growing challenge. Anesthesia Intensive Care 2011; 39:804–823. 10. Gilmore T, Saccheti A, Cortese T. Buprenorphine/naloxone inhibition of remifentanil procedural sedation. Am J Emerg Med 2012; 30:1655e3–1655e4. 11. Wasson M, Beirne OR. Buprenorphine therapy: an increasing challenge in oral & and maxillofacial surgery. Med Manag Pharmacol Update 2013; 116:142–146. The use of nonopioid medications for pain control in the patient maintained on buprenorphine is reviewed in this study. 12. Zakine J, Samarcq D, Lorne E, et al. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg 2008; 106:1856– 1861. 13. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo controlled, multicenter randomized trial. Lancet 2011; 377:1506–1513. 14. Vickers AP, Jolly A. Naltrexone and problems in pain management. Br Med J 2006; 332:132–133. 15. Dean RL, Todtenkopf MS, Deaver DR, et al. Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone. Pharmacol Biochem Behav 2008; 89:515–522. 16. Bond AJ, Reed KDF, Beavan P, Strang J. After the randomized injectable & opiate treatment trial: posttrial investigation of slow-release oral morphine as an alternative to opiate maintenance medication. Drug Alcohol Rev 2013; 31:492–498. Patients who present having taken SROM for opioid dependence may be treated the same as any opioid-tolerant patient, as this particular formulation of morphine has no unique effects.
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