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Sublingual Buprenorphine
PHARMACOLOGY FACTS
Sublingual Buprenorphine Julie Golembiewski, PharmD, Andrei M. Rakic, MD OPIOID-DEPENDENT PATIENTS present a unique perioperative care challenge. These patients are managed as outpatients in several different manners. The type of treatment that such patients receive can have a profound impact on their perioperative care when they present for surgery. One management option is the use of sublingual (SL) buprenorphine to treat opioid dependence. This drug is available as either Suboxone or Subutex (Reckitt Benckiser Pharmaceuticals, Inc, Richmond, VA). Subutex contains buprenorphine only, whereas Suboxone contains buprenorphine and naloxone to deter diversion to the injectable route (naloxone will precipitate opioid withdrawal if injected, but has no effect if taken sublingually or orally). As we shall see, the same properties that make buprenorphine effective in the treatment of opioid addiction can confound perioperative pain management of the patient taking this drug. A basic appreciation of this unique drug is important in providing optimal perioperative care and alerting caretakers of the need for appropriate consultation.
Pharmacology of Sublingual Buprenorphine Traditional opioids (eg, morphine) are strong activators of opioid receptors. Naloxone is a potent blocker of opioid receptors. Buprenorphine produces an effect between these two extremes. Therapeutically, buprenorphine activates opioid
Julie Golembiewski, PharmD, is a Clinical Associate Professor, Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, IL; and Andrei M. Rakic, MD, is an Associate Professor of Clinical Anesthesiology, University of Illinois at Chicago College of Medicine, Chicago, IL. Address correspondence to Dr. Julie Golembiewski, Department of Anesthesiology, University of Illinois Medical Center, Suite 3200 (MC 515), 1740 West Taylor Street, Chicago, IL 60612-7239; e-mail address: [email protected]. Ó 2010 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 doi:10.1016/j.jopan.2010.09.007
receptors to a lesser extent than morphine. As such, it prevents symptoms of opioid withdrawal when a patient is taking the drug. Buprenorphine binds to opioid receptors so aggressively that it blocks other opioids (eg, morphine) from exerting any additional effect. A combination of the (relatively high) doses used to treat opioid dependence and the aggressive binding of buprenorphine to opioid receptors gives SL buprenorphine a very long half-life (duration of action). Because of this, a patient taking SL buprenorphine is unable to gain any effect from taking any other opioid agonist. In this manner, buprenorphine acts as a deterrent to drug abuse. Hence, we see that the effect of SL buprenorphine is dependent on the presence of other drugs. That is, when taken alone, SL buprenorphine prevents withdrawal, but if other opioids are present, it blocks their action. These mixed effects are why buprenorphine is referred to as a ‘‘mixed agonist–antagonist’’ or, more specifically, a ‘‘partial opioid agonist.’’1,2 To understand how buprenorphine affects perioperative pain management, it is important to understand its ‘‘weak agonist’’ properties. At low doses, both morphine and buprenorphine are similar in that an increase in dose will yield an increase in effect. (For the purposes of this discussion, the opioid effects of interest are analgesia and respiratory depression.) As the dose of morphine is increased, both analgesia and respiratory depression also increase. This allows for profound analgesia with morphine, but at the risk of severe respiratory depression, possibly leading to respiratory arrest and death. In contrast, increasing the buprenorphine dose beyond a certain point (24 mg/day of SL buprenorphine) yields no additional drug effect—neither analgesia nor respiratory depression.1,3 This is termed a ceiling effect (Fig 1). The ceiling effect offers buprenorphine the following advantages over other opioids in the management of addiction: (1) lower abuse potential, (2) lower level of physical dependence/withdrawal
Journal of PeriAnesthesia Nursing, Vol 25, No 6 (December), 2010: pp 413-415
413
GOLEMBIEWSKI AND RAKIC
414
Conceptual Representation of the Dose-Response Curve of Morphine and Buprenorphine Morphine Buprenorphine
Full Agonist (Morphine)
Opioid Effect
Nalox one
Ceiling effect *
Dose A
Partial Agonist (Buprenorphine)
Full Antagonist (Naloxone)
Dose
* The effects of morphine (analgesia, respiratory depression) increase with increasing doses. The effects of buprenorphine increase until “Dose A” is reached. No further effect is seen with an increase in dose beyond “Dose A.”
Figure 1. Conceptual representation of the doseresponse curve of morphine and buprenorphine. This figure is available in color online at www.jopan.org.
discomfort, and (3) beyond a certain dose, buprenorphine produces no additional analgesia, respiratory depression, or euphoria.3 These features make buprenorphine safer than methadone in an overdose situation and allow buprenorphine to be used for office-based treatment of opioid dependence.4 Once a stable dose of SL buprenorphine is reached, its long duration of action allows once-a-day dosing and, if the dose is increased further, every-other-day or even three-times-a-week (eg, Monday, Wednesday, Friday) dosing.1,5
because of its long half-life, it takes approximately five to seven days until SL buprenorphine is sufficiently eliminated from the body to allow other opioids to function effectively. The best approach to perioperative management of a patient who has been taking SL buprenorphine is to discontinue it five to seven days before a surgical procedure that will require the use of an opioid for postoperative pain management.6 This will allow enough time for the effects of SL at the opioid receptor to dissipate, and replacement treatment with an opioid (possibly methadone) should be considered to prevent withdrawal symptoms. The use of regional anesthesia techniques (ie, peripheral nerve blocks, epidural analgesia) and nonopioid analgesics (eg, ketamine, ketorolac, gabapentin) should be maximized to provide intraand postoperative analgesia. (In the event of emergency surgery, these will be the only possible options and their use will need to be maximized.) For elective surgeries where buprenorphine has been discontinued before surgery, postoperative administration of intravenous patient-controlled analgesia with an opioid such as morphine can be used to treat postoperative pain and prevent opioid withdrawal syndrome. At the appropriate time after discharge, the patient can be converted back to SL buprenorphine under the management of a physician who has completed the training requirements specified under the Drug Addiction Treatment Act of 2000 (DATA 2000) and who has registered as such with the Drug Enforcement Agency (DEA).
Perioperative Considerations for Patients Taking Sublingual Buprenorphine
Conclusion
Having discussed buprenorphine’s mixed agonist– antagonist properties, its long half-life, and its ceiling effect, we can now consider how it will affect perioperative pain management. When patients on SL buprenorphine undergo surgery, the antagonist properties of buprenorphine render traditional doses of opioids ineffective. Because of its weak agonist property, buprenorphine does not exert a sufficient analgesic effect to meet the needs of most surgical patients. Because of the ceiling effect, giving more buprenorphine will not provide any additional analgesia. This problem is also exacerbated by the fact that patients on buprenorphine will often display tolerance to opioids and may also suffer from hyperalgesia. Finally,
A perioperative management plan is critical for patients taking SL buprenorphine before surgery. Ideally, SL buprenorphine should be discontinued five to seven days before surgery, with titration of an appropriate full opioid agonist if necessary. The anesthesia care provider and acute pain management service should be consulted ahead of time. The need for regional and nonopioid analgesia for perioperative pain management should be preempted and maximized. When the patient’s pain is able to be controlled with an oral nonopioid (eg, ibuprofen, acetaminophen), SL buprenorphine may be restarted by a physician trained under the DATA 2000 requirements and who is registered with the DEA.
PHARMACOLOGY FACTS: SUBLINGUAL BUPRENORPHINE
415
References 1. Johnson RE, Strain EC, Amass L. Buprenorphine: How to use it right. Drug Alcohol Depend. 2003;70:S59-S77. 2. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: Extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70:S13-S27. 3. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: Ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.
4. Dasgupta N, Bailey EJ, Cicero T, et al. Post-marketing surveillance of methadone and buprenorphine in the United States. Pain Med. 2010;11:1078-1091. 5. Jones HE. Practical considerations for the clinical use of buprenorphine. Sci Pract Perspect. 2004;2:4-20. 6. Savage SR, Kirsh KL, Passik ST. Challenges in using opioids to treat pain in persons with substance use disorders. Addict Sci Clin Pract. 2008;4:4-25.
Sublingual Buprenorphine Julie Golembiewski, PharmD, Andrei M. Rakic, MD OPIOID-DEPENDENT PATIENTS present a unique perioperative care challenge. These patients are managed as outpatients in several different manners. The type of treatment that such patients receive can have a profound impact on their perioperative care when they present for surgery. One management option is the use of sublingual (SL) buprenorphine to treat opioid dependence. This drug is available as either Suboxone or Subutex (Reckitt Benckiser Pharmaceuticals, Inc, Richmond, VA). Subutex contains buprenorphine only, whereas Suboxone contains buprenorphine and naloxone to deter diversion to the injectable route (naloxone will precipitate opioid withdrawal if injected, but has no effect if taken sublingually or orally). As we shall see, the same properties that make buprenorphine effective in the treatment of opioid addiction can confound perioperative pain management of the patient taking this drug. A basic appreciation of this unique drug is important in providing optimal perioperative care and alerting caretakers of the need for appropriate consultation.
Pharmacology of Sublingual Buprenorphine Traditional opioids (eg, morphine) are strong activators of opioid receptors. Naloxone is a potent blocker of opioid receptors. Buprenorphine produces an effect between these two extremes. Therapeutically, buprenorphine activates opioid
Julie Golembiewski, PharmD, is a Clinical Associate Professor, Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, IL; and Andrei M. Rakic, MD, is an Associate Professor of Clinical Anesthesiology, University of Illinois at Chicago College of Medicine, Chicago, IL. Address correspondence to Dr. Julie Golembiewski, Department of Anesthesiology, University of Illinois Medical Center, Suite 3200 (MC 515), 1740 West Taylor Street, Chicago, IL 60612-7239; e-mail address: [email protected]. Ó 2010 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 doi:10.1016/j.jopan.2010.09.007
receptors to a lesser extent than morphine. As such, it prevents symptoms of opioid withdrawal when a patient is taking the drug. Buprenorphine binds to opioid receptors so aggressively that it blocks other opioids (eg, morphine) from exerting any additional effect. A combination of the (relatively high) doses used to treat opioid dependence and the aggressive binding of buprenorphine to opioid receptors gives SL buprenorphine a very long half-life (duration of action). Because of this, a patient taking SL buprenorphine is unable to gain any effect from taking any other opioid agonist. In this manner, buprenorphine acts as a deterrent to drug abuse. Hence, we see that the effect of SL buprenorphine is dependent on the presence of other drugs. That is, when taken alone, SL buprenorphine prevents withdrawal, but if other opioids are present, it blocks their action. These mixed effects are why buprenorphine is referred to as a ‘‘mixed agonist–antagonist’’ or, more specifically, a ‘‘partial opioid agonist.’’1,2 To understand how buprenorphine affects perioperative pain management, it is important to understand its ‘‘weak agonist’’ properties. At low doses, both morphine and buprenorphine are similar in that an increase in dose will yield an increase in effect. (For the purposes of this discussion, the opioid effects of interest are analgesia and respiratory depression.) As the dose of morphine is increased, both analgesia and respiratory depression also increase. This allows for profound analgesia with morphine, but at the risk of severe respiratory depression, possibly leading to respiratory arrest and death. In contrast, increasing the buprenorphine dose beyond a certain point (24 mg/day of SL buprenorphine) yields no additional drug effect—neither analgesia nor respiratory depression.1,3 This is termed a ceiling effect (Fig 1). The ceiling effect offers buprenorphine the following advantages over other opioids in the management of addiction: (1) lower abuse potential, (2) lower level of physical dependence/withdrawal
Journal of PeriAnesthesia Nursing, Vol 25, No 6 (December), 2010: pp 413-415
413
GOLEMBIEWSKI AND RAKIC
414
Conceptual Representation of the Dose-Response Curve of Morphine and Buprenorphine Morphine Buprenorphine
Full Agonist (Morphine)
Opioid Effect
Nalox one
Ceiling effect *
Dose A
Partial Agonist (Buprenorphine)
Full Antagonist (Naloxone)
Dose
* The effects of morphine (analgesia, respiratory depression) increase with increasing doses. The effects of buprenorphine increase until “Dose A” is reached. No further effect is seen with an increase in dose beyond “Dose A.”
Figure 1. Conceptual representation of the doseresponse curve of morphine and buprenorphine. This figure is available in color online at www.jopan.org.
discomfort, and (3) beyond a certain dose, buprenorphine produces no additional analgesia, respiratory depression, or euphoria.3 These features make buprenorphine safer than methadone in an overdose situation and allow buprenorphine to be used for office-based treatment of opioid dependence.4 Once a stable dose of SL buprenorphine is reached, its long duration of action allows once-a-day dosing and, if the dose is increased further, every-other-day or even three-times-a-week (eg, Monday, Wednesday, Friday) dosing.1,5
because of its long half-life, it takes approximately five to seven days until SL buprenorphine is sufficiently eliminated from the body to allow other opioids to function effectively. The best approach to perioperative management of a patient who has been taking SL buprenorphine is to discontinue it five to seven days before a surgical procedure that will require the use of an opioid for postoperative pain management.6 This will allow enough time for the effects of SL at the opioid receptor to dissipate, and replacement treatment with an opioid (possibly methadone) should be considered to prevent withdrawal symptoms. The use of regional anesthesia techniques (ie, peripheral nerve blocks, epidural analgesia) and nonopioid analgesics (eg, ketamine, ketorolac, gabapentin) should be maximized to provide intraand postoperative analgesia. (In the event of emergency surgery, these will be the only possible options and their use will need to be maximized.) For elective surgeries where buprenorphine has been discontinued before surgery, postoperative administration of intravenous patient-controlled analgesia with an opioid such as morphine can be used to treat postoperative pain and prevent opioid withdrawal syndrome. At the appropriate time after discharge, the patient can be converted back to SL buprenorphine under the management of a physician who has completed the training requirements specified under the Drug Addiction Treatment Act of 2000 (DATA 2000) and who has registered as such with the Drug Enforcement Agency (DEA).
Perioperative Considerations for Patients Taking Sublingual Buprenorphine
Conclusion
Having discussed buprenorphine’s mixed agonist– antagonist properties, its long half-life, and its ceiling effect, we can now consider how it will affect perioperative pain management. When patients on SL buprenorphine undergo surgery, the antagonist properties of buprenorphine render traditional doses of opioids ineffective. Because of its weak agonist property, buprenorphine does not exert a sufficient analgesic effect to meet the needs of most surgical patients. Because of the ceiling effect, giving more buprenorphine will not provide any additional analgesia. This problem is also exacerbated by the fact that patients on buprenorphine will often display tolerance to opioids and may also suffer from hyperalgesia. Finally,
A perioperative management plan is critical for patients taking SL buprenorphine before surgery. Ideally, SL buprenorphine should be discontinued five to seven days before surgery, with titration of an appropriate full opioid agonist if necessary. The anesthesia care provider and acute pain management service should be consulted ahead of time. The need for regional and nonopioid analgesia for perioperative pain management should be preempted and maximized. When the patient’s pain is able to be controlled with an oral nonopioid (eg, ibuprofen, acetaminophen), SL buprenorphine may be restarted by a physician trained under the DATA 2000 requirements and who is registered with the DEA.
PHARMACOLOGY FACTS: SUBLINGUAL BUPRENORPHINE
415
References 1. Johnson RE, Strain EC, Amass L. Buprenorphine: How to use it right. Drug Alcohol Depend. 2003;70:S59-S77. 2. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: Extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70:S13-S27. 3. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: Ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.
4. Dasgupta N, Bailey EJ, Cicero T, et al. Post-marketing surveillance of methadone and buprenorphine in the United States. Pain Med. 2010;11:1078-1091. 5. Jones HE. Practical considerations for the clinical use of buprenorphine. Sci Pract Perspect. 2004;2:4-20. 6. Savage SR, Kirsh KL, Passik ST. Challenges in using opioids to treat pain in persons with substance use disorders. Addict Sci Clin Pract. 2008;4:4-25.