Perioperative implications of buprenorphine maintenance treatment for addiction more

Perioperative Implications of Buprenorphine Maintenance Treatment for Opioid Addiction Clifford Gevirtz, MD, MPH* Louisiana State University Health Sciences Center New Orleans, Louisiana Elizabeth A.M. Frost, MDw Ethan O. Bryson, MDw Mount Sinai Medical Center New York, New York Prescription drug abuse, including drugs such as oxycontin, percocet, and vicodin, has reached epidemic proportions in the United States. Patients who are opiate dependent can be very demanding and challenging to care for. Chronic opiate use results in marked changes in neurophysiology and limits the effectiveness of many anesthetic medications. Buprenorphine has recently been introduced to treat opiate abuse, and it requires substantial change in how patients are managed in the perioperative period. Buprenorphine is a semisynthetic opioid thebaine derivative with extremely high binding affinity at the m-opioid and k-opioid receptors. It was first marketed by Reckitt and Colman in the 1980s as an analgesic used to treat moderate pain, formulated as a sublingual tablet (Temgesic) and an injectable product (Buprenex) available in microgram doses. In higher dosages (current formulations are available in 2 mg and 8 mg doses), buprenorphine has the curious property of blocking other opioids from binding to the m-opioid and k-opioid receptors, preventing the addicted patient, who is maintained on buprenorphine, from experiencing the ‘‘high’’ associated with heroin or other opioids, thus discouraging illicit opioid abuse.1 Buprenorphine, as FROM THE *DEPARTMENT OF ANESTHESIOLOGY AND THE wDEPARTMENT OF ANESTHESIA REPRINTS: ETHAN O. BRYSON, MD, DEPARTMENT OF ANESTHESIA, MOUNT SINAI MEDICAL CENTER, NY. E-MAIL: ETHAN.BRYSON@MOUNTSINAI.ORG INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 49, Number 1, 147–155 r 2011, Lippincott Williams & Wilkins www.anesthesiaclinics.com | 147 148 ’ Gevirtz et al a treatment for opioid addiction, is available as Subutex (Reckitt Benckiser, Bristol, UK) and the buprenorphine/naloxone combination as Suboxone (Reckitt Benckiser). ’ Prevalence of Opioid Abuse and Treatment It is estimated that only 12% to 15% of the opioid-dependent population in the United States are enrolled in a methadone maintenance program.2 The stigma attached to such programs has likely contributed to this low number. Unlike other opioid-abuse treatments, buprenorphinebased formulations can be legally prescribed and managed by clinicians in an office-based setting. Although methadone administration must be witnessed and dispensed in small incremental doses each time initially, the Drug Addiction Treatment Act of 2000 (DATA 2000) now allows physicians to prescribe buprenorphine to opioid addicts, provide them with a month’s supply at a time, and allows patients to self administer the drug. Unlike methadone maintenance programs, which require witnessed administration and considerable patient monitoring, buprenorphine maintenance allows patients to avoid the stigma of intense ongoing monitoring and observation. Buprenorphine is nearly ideal for detoxification, as it can be adjusted rapidly with minimal risk for inducing severe consequences. Buprenorphine also has a small abuse potential when combined with naloxone. When using this combination product, attempts to abuse the drug by snorting, smoking, injecting, cooking, or dissolving the tablet in alcohol, releases the antagonist drug naloxone into the systemic circulation, which will result in the development of the withdrawal syndrome in opioid-dependent patients. Both, the increased access to treatment and the improved safety profile, make buprenorphine/ naloxone an attractive and significant treatment option for addicts. On account of the safety profile of buprenorphine, it is the first opioid treatment option that can be managed and prescribed by trained physicians in an office-based setting. This management allows patients to live a more regular life while getting treatment for their addiction and avoids the stigma involved in the use of methadone. ’ Characteristics of Buprenorphine/Naloxone Buprenorphine is gaining widespread acceptance. Although there are an estimated 1.2 million patients dependent on illicit opioids in 2005 in the United States,3 approximately 100,000 have been started on buprenorphine treatment.4 According to the manufacturer, by 2008, the estimate for use worldwide had risen to more than 400,000 patients.5 Currently, buprenorphine is sold under the trade name of Suboxone, which is a formulation of buprenorphine and naloxone, in a 4:1 ratio. www.anesthesiaclinics.com Perioperative Implications of Buprenorphine Maintenance Treatment ’ 149 Subutex is a formulation that contains only buprenorphine and is for the initial induction onto the partial agonist drug during the detoxification process from illicit or prescription pain medications. In the combination form, the naloxone added to the buprenorphine formulation serves to prevent diversion and subsequent misuse through the parenteral or intranasal routes. The naloxone is not absorbed in clinically relevant amounts by the patient through the buccal mucosa if taken sublingually as directed, thus, leaving the opioid-agonist effects of buprenorphine to predominate. However, naloxone does not totally prevent diversion; in fact, the buprenorphine/naloxone product has some value on the street for preventing the effects of withdrawal associated with opioid abuse when illicit opioids of choice (eg, heroin, opium) are not available. When taken parenterally by patients physically dependent on full agonist opioids, the opioid-antagonist naloxone will cause the withdrawal syndrome. Suboxone is listed as a Schedule III drug under the Controlled Substances Act. Just before to the approval by the Food and Drug Administration, Suboxone was rescheduled from Schedule V, the schedule with the lowest restriction and penalties for misuse, to Schedule III, because of its potential for diversion and abuse. Under this classification, any doctor, after completing a training course, can prescribe buprenorphine/naloxone to opioid addiction in the office. The training process is simple and requires practitioners to participate in a defined 8-hour continuing medical educational program and then send a formal notice to the Secretary of Health and Human Services that he or she intends to prescribe these medications for detoxification purposes. A separate registration is not required if the medication is prescribed for intraoperative or pain-management purposes only. Similarly, the intravenous form is specifically labeled as ‘‘not for detoxification.’’ ’ Drug Testing A major problem with buprenorphine exists in trauma patients in which the medication history may be unknown. Most Clinical Laboratory Improvement Amendments waived testing kits will not detect buprenorphine or its metabolites in urine. Specifically requested urine and blood testing is required to detect buprenorphine. This may require the specimen be sent to an outside laboratory with an attendant delay in obtaining a result. ’ Pharmacology and Pharmacokinetics of Buprenorphine/Naloxone Buprenorphine action results from its partial agonist activity at the m-opioid receptors, and antagonist activity at the e-opioid and k-opioid www.anesthesiaclinics.com 150 ’ Gevirtz et al receptors. It has a very high potency, 25 to 50 times higher than morphine, but its effects as a full opioid agonist are lower, giving it a more favorable safety profile than methadone.6 The agonist effects of buprenorphine plateau at higher doses, creating a ceiling effect which allows for a much larger therapeutic window. Buprenorphine binds 1000 times more tightly to m-opioid and k-opioid receptors than morphine, and slowly dissociates from the receptors. Although it takes only 7 minutes for half of an administered dose of fentanyl to disassociate from the opioid receptors, half of an equivalent dose of buprenorphine will take 166 minutes to dissociate. Buprenorphine metabolism primarily occurs in the liver by the CYP3A4 and CYP2C8 isozymes of the cytochrome P450 system, into norbuprenorphine by N-dealkylation. Buprenorphine and norbuprenorphine are eliminated mainly through excretion into the bile after glucuronidation by UGT1A1 and UGT2B7, or by UGT1A1 and UGT1A3; therefore, it may be safely administered to patients with renal insufficiency. Hand et al7 studied buprenorphine clearance in patients with normal and impaired renal clearance and found the values were similar enough to be not clinically significantly different (934 and 1102 mL/min, respectively), as were dose-corrected plasma concentrations of buprenorphine measured. In patients with renal failure, plasma concentrations of norbuprenorphine were increased approximately 4 times, and buprenorphine 3-gluconate concentrations by almost 15 times. But as these metabolites are not clinically active, there is no need to modify the doses in patients with in renal insufficiency. Berson et al8 reported 4 cases of former heroin addicts infected with hepatitis C virus and who had been placed on substitution therapy with buprenorphine. These patients exhibited a marked increase in serum alanine aminotransferase after injecting buprenorphine intravenously, and 3 of them also developed jaundice. Stopping these buprenorphine injections was associated with prompt recovery, although 2 of these patients continued ingesting buprenorphine by the sublingual route. A fifth patient infected with the hepatitis C and human immunodeficiency viruses, developed jaundice and asterixis with panlobular liver necrosis and microvesicular steatosis after using sublingual buprenorphine along with small doses of aminoacetophen and aspirin. They concluded that although buprenorphine hepatitis is uncommon even after intravenous misuse, addicts placed on buprenorphine should be repeatedly warned not to use it intravenously. In summary, higher drug concentrations (greater than 12 mg/d) can trigger hepatitis in intravenous users, possibly if mitochondrial function is already compromised by viral infections and other factors. This issue was further studied by Petry et al,9 who assessed changes in liver enzyme levels among opioid-dependent patients treated with buprenorphine. Liver enzyme levels were evaluated in 120 individuals www.anesthesiaclinics.com Perioperative Implications of Buprenorphine Maintenance Treatment ’ 151 before and then after a minimum of 40 days of buprenorphine treatment (2, 4, or 8 mg/70 kg/d). In patients with a history of hepatitis, aspartate aminotransferase (AST) and alanine aminotransferase levels significantly increased (P<0.05) with buprenorphine treatment. The odds of observing an increase in AST were directly correlated with increasing buprenorphine dose (P< 0.05; odds ratio = 1.23 per 1 mg increase in dose). These results suggest that liver enzyme levels should be monitored frequently when patients with hepatitis are treated with buprenorphine. Anesthesiologists would be well advised to use agents that are not extensively metabolized by the liver and to use techniques that maintain hepatic blood flow. It should also be noted that the Sphincter of Oddi will constrict in the presence of buprenorphine and this may also result in elevation of AST and alanine aminotransferase levels. Doses as high as 4 to 8 mg sublingually are now considered appropriate for treatment of moderate-to-severe pain. The usual maximum recommended dose is 24 mg/day, and is required only for those patients who were on large doses of opiates previously, e.g. greater than 200 mg of methadone or 300 mg of morphine per day. The pharmacodynamics of buprenorphine require a slower titration for pain relief, that is adding 4 mg every 20 minutes, rather than resorting immediately straight to the maximum dose. It is best to ‘‘go low and go slow,’’ as respiratory depression can occur and is not easily reversed. ’ Special Considerations for Acute and Chronic Pain Control Although there are very limited published data involving patients on buprenorphine who present for procedures or surgery requiring anesthesia, case reports lend guidance for the management of perioperative pain. The successful management of postcesarean section pain in 2 patients maintained on buprenorphine was achieved using intravenous morphine patient-controlled analgesia with oral oxycodone for breakthrough pain at markedly elevated doses.10 In both cases, the patients were able to continue buprenorphine therapy throughout their hospital stay. Each patient was able to achieve acceptable levels of pain control with a total dose of 180 mg/day of morphine. When switched to oral medications, 1 patient was able to achieve pain relief with 60 mg/day of oxycodone and 6000 mg of acetaminophen; however, the second patient required an additional 600 mg of ibuprofen every 8 hours with this regimen. None of the patient breast-fed their infant. Supplemental doses of sublingual buprenorphine have successfully been used to control postoperative pain in a patient maintained on buprenorphine.11 As an example, a patient received general anesthesia for the removal of breast implants and used supplemental buprenorphine, 2 to 4 mg every 4 to 6 hours, in addition to her 24 mg-per-day www.anesthesiaclinics.com 152 ’ Gevirtz et al maintenance dose, as needed for pain. She was able to achieve adequate pain relief with supplemental buprenorphine, requiring a total dose of 72 mg on postoperative day 1, and then tapered back to 24 mg per day by postoperative day 11. Recommendations have been proposed for the control of acute pain in the patient maintained on buprenorphine:12  Use shorter acting opioid analgesics in addition to the maintenance dose of buprenorphine and titrating to achieve effective pain control.  Divide the total buprenorphine maintenance dose over the course of 24 hours and relying solely on the analgesic properties of buprenorphine.  Replace the buprenorphine with methadone and then adding another short acting opioid analgesic for breakthrough pain.  Replace the buprenorphine with another opioid analgesic (eg, intravenous fentanyl or morphine) altogether.  Add regional anesthetic blockade where possible. However in general, patients maintained on buprenorphine typically require much higher doses of opioid agonists throughout the postoperative course to achieve adequate pain relief. The use of epidural and intrathecal buprenorphine have been reported anecdotally only. The real danger here is that accidental respiratory depression cannot be reliably reversed with either naloxone or nalmefene. ’ Options for Postoperative Pain Control in Buprenorphine Maintenance Patients Some patients on buprenorphine may wish to avoid opioids, if at all possible, because of the perceived risk of rekindling opiate addiction. If a patient is on buprenorphine maintenance therapy, several options for intraoperative and postoperative pain control can be considered, including pre-emptive administration of celecoxib or pregabalin, preloading of the incision sites with local anesthetic before incision, placement of an epidural catheter for intraoperative and postoperative use, and postoperative ketorolac administration. High-dose buprenorphine used for opioid substitution has a long half-life, which combines with its strong affinity for the m-opioid receptor and slow receptor dissociation to account for the long duration of action of the drug.13 Studies have shown that the opioid-blocking action of buprenorphine can persist for several days after discontinuation of the medication, which would make conventional opiate pain therapy difficult or impossible. In 1 study of male patients with a recent history of opioid addiction, sublingual buprenorphine, at a dose of 8 mg daily www.anesthesiaclinics.com Perioperative Implications of Buprenorphine Maintenance Treatment ’ 153 for 1 week, blocked the subjective and respiratory depressant effects of hydromorphone (4 mg) intramuscularly for up to 5 days after discontinuation of the buprenorphine.14 As buprenorphine is a partial agonist, patients maintained on this drug have a significantly increased tolerance for opioids and may require extremely high doses to achieve analgesia. This affinity of buprenorphine for m-opioid receptors is so high that it has been reportedly used to reverse heroin overdose.15 No controlled trials have been conducted which show the extent to which doses of particular opioid agonists required to achieve analgesia are increased for patients maintained on buprenorphine. One option for treatment of acute pain is to increase the dose of buprenorphine itself, although there is a significant ‘‘ceiling effect,’’ and if analgesia is not achieved, other options need to be considered. The use of nonopioid analgesics (eg, tricyclic antidepressants, anticonvulsants such as gabapentin), local or regional techniques, or a combination of technique may prove effective. ’ Special Considerations for Use in Children Michel and Zernikow16 reviewed pediatric pharmacologic data on buprenorphine, especially with respect to the long-term application in children suffering from chronic pain after repeated sublingual or longterm transdermal administration. Compared with adults, after singledose buprenorphine, children exhibit a larger clearance to body weight ratio but a paradoxically longer duration of action. If combined with other opioids or sedatives or if the metabolite norbuprenorphine cumulates, it is difficult to predict the risk of respiratory depression. It is emphasized that clear-cut evidence is missing in children that there is a ceiling of buprenorphine-induced respiratory depression. Owing to its various application routes, long duration of action, and metabolism largely independent of renal function, buprenorphine is of special clinical interest in pediatrics, especially for postoperative pain and cancer pain control. Geib et al17 published a case series of 5 infants with respiratory and mental-status depression after unintentional buprenorphine exposure. Despite buprenorphine partial agonist activity and ceiling effect on respiratory depression, all children required hospital admission and either opioidantagonist therapy or mechanical ventilation. Results of routine urine toxicology screening for opioids were negative in all cases. Confirmatory testing for buprenorphine ingestion was only sent for 1 child and returned with a positive result. As the use of buprenorphine in homebased therapy for opioid addiction increases in the United States, a public health concern for the pediatric population arises and patients need to be warned to specifically take precautions to prevent the accidental ingestion by children. www.anesthesiaclinics.com 154 ’ Gevirtz et al Johnson et al18 discovered an advantage for the newborn when they conducted a meta-analysis of the incidence of withdrawal symptoms when born to a mother dependent on buprenorphine. Although an estimated 55% to 94% of infants born to opioid-dependent mothers in United States show signs of opioid withdrawal during the neonatal period, buprenorphine has been reported to produce little or no autonomic signs or symptoms of opioid withdrawal after abrupt termination in adults. The investigators conducted a meta-analysis with 21 published reports representing approximately 15 evaluable cohorts of infants exposed to buprenorphine in utero. The neonatal abstinence syndrome (NAS) was reported in 62% infants of the 309 infants exposed, with 48% requiring treatment; However, greater than 40% of these cases had confounding factors because of the use of other illicit drugs. The NAS associated with buprenorphine generally appears within 12 to 48 hours, peaks at approximately 72 to 96 hours, and lasts for 120 to 168 hours. These symptoms are quantifiably less severe than those observed after in utero exposure to methadone. On the basis of this review of the literature, buprenorphine appears to be safe and effective in both mother and infant, with a NAS that is less severe than methadone withdrawal both qualitatively and quantitatively. As there is a lack of comprehensive data on the safety of buprenorphine during pregnancy, pregnant women who conceive while on buprenorphine treatment should consider transferring to methadone. However, some pregnant women may decline this option due to social issues. There may also arise clinical situations in which it may be advisable for a pregnant woman to continue buprenorphine during pregnancy rather than risk a relapse to illicit heroin use. These risks include seroconversion with human immunodeficiency viruses and hepatitis B and C while balancing the potential unknown dangers of buprenorphine. The dangers of maintaining illicit heroin use during pregnancy, thus, may well be significantly greater than the risks of buprenorphine maintenance for these women and their babies. The substantial body of knowledge of the safety of methadone treatment during pregnancy must also be added to the calculus of decision-making. ’ Conclusions Buprenorphine in combination with naloxone is being prescribed to a growing number of patients. As buprenorphine is a partial opioid agonist with high affinity for m-opioid receptors, patients maintained on this agent are prevented from experiencing much of the euphoria associated with illicit opioid use, but they will require substantially higher doses of opioids or innovative alternate methods to achieve adequate pain control. The adroit and knowledgeable anesthesiologist can make a substantial impact in the care of these difficult patients. www.anesthesiaclinics.com Perioperative Implications of Buprenorphine Maintenance Treatment ’ ’ 155 References 1. Ling W. Buprenorphine for opioid dependence. Expert Rev. Neurother. 2009;9: 609–616. 2. Raisch DW, Fye CL, Boardman KD, et al. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother. 2002;36:312–321. 3. Rockville MD. National Survey on Drug Use and Health, 2005. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2006. 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