US Pharm. 2014;39(10):HS16-HS20.
ABSTRACT: The buprenorphine transdermal patch (Butrans) is approved for use in patients with pain severe enough to require daily, around-the-clock, long-term opioid use when other treatment options are not adequate. Buprenorphine works as a partial agonist at the mu-opioid receptor. There are five different buprenorphine patch strengths. Patients who either are opioid-naïve or using other opioids may be initiated on or converted to the buprenorphine transdermal patch. Adverse effects are consistent with those of other opioids and include, but are not limited to, nausea and vomiting, dizziness, constipation, and somnolence. Patients should receive education regarding appropriate patch application, use, and disposal. The buprenorphine transdermal patch is included under the Risk Evaluation
and Mitigation Strategy (REMS).
The buprenorphine transdermal patch (Butrans) is FDA-indicated for use in patients with pain that is severe enough to require daily, around-the-clock, long-term opioid use for which other treatments are not adequate. Given the risks of addiction, abuse, and misuse with opioids, as well as the increased risk of overdose and death with use of extended-release opioids, the buprenorphine transdermal patch should be reserved for use in patients for whom alternative treatments, such as nonopioid options or immediate-release opioids, are not effective, not tolerated, or not adequate for pain management. The buprenorphine patch should not be used as an as-needed medication.1
Buprenorphine is a semisynthetic opioid.2 Unlike other opioids, such as morphine, which work as full agonists at the mu-opioid receptor, buprenor-phine works as a partial agonist on the mu-opioid receptors while also acting as an antagonist at the kappa-opioid receptors, an agonist at the delta-opioid receptors, and a partial agonist at the opioid receptor-like (ORL-1) receptors.1,3
Mu-opioid receptors are associated with supraspinal analgesia in addition to respiratory depression, euphoria, sedation, decrease in gastrointestinal (GI) motility, and physical dependence. Kappa receptors are associated with spinal analgesia, sedation, dyspnea, dependence, dysphoria, and respiratory depression, while delta receptors may be associated with analgesia as well as psychomimetic effects and dysphoria.4,5 ORL-1 receptors are similar in structure to opioid receptors and may be involved in central modulation of pain.5
The affinity of a drug indicates the strength of receptor binding, whereas the intrinsic activity is associated with the degree to which the drug activates the receptor it is binding to.6 Buprenorphine has a high affinity at the mu-opioid receptor; however, it has low intrinsic activity. The receptor affinity at the ORL-1 receptors has been shown to be notably lower.7 Buprenorphine has slow association with and dissociation from the receptor, resulting in a longer onset time and duration of action.8
Steady state is achieved by the third day of buprenorphine patch use. The bioavailability of the buprenorphine patch is noted to be 15%. The volume of distribution is large, and buprenorphine is 96% plasma protein–bound. Buprenorphine is metabolized hepatically by N-dealkylation via CYP3A4 and glucuronidation by UGT-isoenzymes. The terminal half-life is about 26 hours. It is primarily excreted in the feces (70%).1
Dosing and Available Strengths
Per the manufacturer, opioid-naïve patients may be initiated on the buprenorphine patch at a dosage of 5 mcg/h. For patients who are already on opioid therapy, the total daily oral morphine (or morphine-equivalent) dosage must be calculated. If a patient was taking <30 mg of oral morphine or its equivalent, the 5-mcg/h patch may be initiated. If the total daily dosage of oral morphine (or morphine-equivalent) is 30 to 80 mg, the patient’s opioid(s) must be tapered for up to 7 days to no more than 30 mg of oral morphine (or its equivalent) per day prior to initiating the buprenorphine patch at 10 mcg/h; otherwise, there is a potential for withdrawal to occur. Short-acting analgesics may be used as needed in the interim until analgesia with the buprenorphine patch is obtained. When the buprenorphine transdermal patch is initiated, all other around-the-clock opioids should be discontinued. The patch is worn for 7 days. Of note, patients using >80 mg of oral morphine (or morphine equivalent) per day may not achieve sufficient analgesia with the buprenorphine 20 mcg/h transdermal patch; providers should consider alternative analgesic options. TABLE 1 summarizes the manufacturer’s dosing recommendations.1
The buprenorphine patch dosage may be titrated after at least 72 hours; the dosage may be adjusted by 5 mcg/h, 7.5 mcg/h, or 10 mcg/h increments. Up to two of the 5-mcg/h, 7.5-mcg/h, or 10-mcg/h patches may be used, and the total buprenorphine dosage should not exceed 20 mcg/h. When patients use two patches, they should remove their current patch, then apply the two new patches at the same time (adjacently) at a different application site.1
With the recent approval of the 7.5-mcg/h patch, there are now five buprenorphine patch strengths: 5, 7.5, 10, 15, and 20 mcg/h. The use of the buprenorphine transdermal patch at the dosage of 40 mcg/h was found to prolong the mean QTc interval by up to 9.2 msec. In the United States, dosages >20 mcg/h should not be used due to the potential to increase the risk of QT interval prolongation.1 Outside the U.S., the buprenorphine patch is available in higher strengths (35, 52.5, and 70 mcg/h) and is used at a shorter dosing interval of every 96 hours.2,9
If the buprenorphine patch is to be discontinued, the dosage should gradually be tapered down every 7 days to avoid the potential for withdrawal symptoms.1 Examples of withdrawal symptoms include dysphoria, restlessness, rhinorrhea, lacrimation, myalgia, arthralgia, nausea, vomiting, abdominal cramping, or diarrhea.10
There are no specific dosage adjustments defined for patients with renal or hepatic impairment, or for elderly patients. In patients with severe hepatic impairment, it is recommended to consider alternative options. Caution is recommended when considering the use of the buprenorphine patch in an elderly patient.1
The most common adverse effects reported with use of the buprenorphine patch include nausea or vomiting, headache, application site reactions, dizziness, constipation, somnolence, and dry mouth.1
Given its mechanism of action, it has been noted that buprenorphine has less potential for respiratory depression compared to full agonists at the mu-opioid receptor, providing that it is dosed appropriately and that other central nervous system (CNS) depressants are not used concomitantly.1,2,6,11 Additionally, some data suggest that buprenorphine may not have an immunosuppressive effect like other opioids, such as morphine and fentanyl.2
Opioid use has been noted to lead to hypogonadism; however, there are some published studies that suggest that buprenorphine may be less likely to cause hypogonadism compared to other opioids.12-15 Two studies compared hormonal effects of oral methadone and sublingual buprenorphine used for maintenance treatment.13,14 One study found no difference in testosterone levels in patients taking between 8 and 20 mg of sublingual buprenorphine per day versus the control group. Testosterone levels in patients taking buprenorphine were significantly greater than those taking methadone 60 to 120 mg per day, and, in turn, buprenorphine patients had less sexual dysfunction.13
Another study also evaluated patients on methadone and buprenorphine maintenance treatment and compared the findings to control groups.14 The mean daily methadone dose was 106 mg while the mean buprenorphine dose was 10.2 mg. While patients on both methadone and buprenorphine were found to have lower free testosterone when compared to the reference groups, patients on methadone had lower total testosterone levels versus the buprenorphine group.14 In addition, one study assessed the effects of the buprenorphine patch (35 mcg/h every 72 hours) on hormone levels in women of reproductive age and in menopausal women. There were no significant changes in total testosterone or free testosterone levels in either group.15
Contraindications, Precautions, and Warnings
Contraindications for use of buprenorphine are similar to those for other opioids and include significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in a setting without resuscitative equipment, paralytic ileus (whether known or suspected), and hypersensitivity to the medication.1
There are four black box warnings for the buprenorphine transdermal patch: 1) addiction, abuse, and misuse potential; 2) accidental exposure; 3) life-threatening respiratory depression; and 4) neonatal opioid withdrawal syndrome. Buprenorphine is a Schedule III controlled substance, and providers should assess the risks of opioid addiction, abuse, and misuse prior to prescribing the buprenorphine patch and should monitor patients during treatment for signs of addiction, abuse, or misuse.1
Other warnings and precautions are similar to those for other opioids. These include caution with use in elderly, cachectic, and debilitated patients; in chronic pulmonary disease, hepatotoxicity, GI conditions, convulsive or seizure disorders, fever, head injury or increased intracranial pressure; with alcohol, CNS depressants, and illicit substances; in risk of QTc prolongation or hypotension; and in application site, allergic, and anaphylactic reactions. They also advise avoiding the use of external heat and warn patients to avoid driving and operating machinery until they know how they react to this medication.1
Potential buprenorphine drug interactions are outlined in TABLE 2.1
Patient Counseling Points
Patients should be educated on proper buprenorphine patch application, use, and disposal. The patch may be applied to the upper outer arm, upper chest, upper back, or the side of the chest. Either side of the body may be used, which allows for eight potential application sites. The patient should rotate the application site each time the patch is changed, ensuring that the same site is not used again for at least 21 days. If the application site needs to be cleaned prior to applying the patch, the patient may only use water to clean the area (i.e., no lotion, soap, alcohol) and allow the site to dry. The patch should be placed on a hairless site; however, if hair is present, the hair may be cut (patients should not shave the site). In addition, advise patients not to apply the patch to irritated or broken skin. The buprenorphine transdermal patch should not be cut. Patients should press the patch down firmly at the application site with the palm of the hand and hold for 15 seconds (without rubbing the patch) to ensure the patch sticks to the skin.
Advise patients to wash their hands after touching or applying the buprenorphine transdermal patch. Inform patients to avoid exposing the patch to heat (e.g., through use of heating pads, electric blankets, or hot tubs), since this may result in greater absorption of the medication, resulting in an increased risk of overdose or even death. In order to help keep the patch in place, patients may use first-aid tape on the edges of the patch. If this fails, a see-through dressing may be used to cover the patch, such as Tegaderm, to allow the buprenorphine patch to be seen underneath the tape while keeping it in place on the skin.1
Patients should be instructed to remove the old patch prior to applying the new one. The old patch may be disposed of using one of two methods: fold the adhesive sides of the buprenorphine patch together and dispose of it by flushing, or use the Patch-Disposal Unit that is packaged with the patches.1
Pivotal Clinical Trials
There were two pivotal phase III trials that led to the approval of the buprenorphine patch for use in pain. One trial was conducted in opioid-naïve patients and the other in opioid-tolerant patients. These trials are summarized in TABLE 3.16,17
Risk Evaluation and Mitigation Strategy
The buprenorphine patch is also included in the Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). The goal of the REMS is to decrease serious adverse events due to inappropriate prescribing, misuse, and abuse of long-acting opioids. The REMS for these products requires that a medication guide be dispensed to patients. Additionally, it includes Elements to Assure Safe Use, which requires healthcare-provider training on these medications.18
Advantages and Disadvantages
Potential advantages for use of the buprenorphine patch include the convenience of the dosing interval, which allows for once-weekly patch application versus oral opioids that may need to be taken multiple times per day or the fentanyl patch, which is dosed every 72 hours. Additionally, the use of a transdermal patch may be beneficial in patients who are unable to swallow or in patients with nausea or vomiting.19 Keeping the patch on for 1 week allows patients to maintain more consistent blood levels versus using oral medications, which result in more frequent peaks and troughs.20 Disadvantages for the use of the buprenorphine transdermal patch include the slow onset of action and, in turn, the long elimination period.8,19
The buprenorphine transdermal patch may be a potential alternative for patients requiring around-the-clock opioid therapy. Providers and patients should be aware that potential adverse effects and precautions are similar to those of other opioid medications. Patients should be educated on the proper application, use, and disposal of this product.
1. Butrans (buprenorphine transdermal system) package insert. Stamford, CT: Purdue Pharma LP; June 2014.
2. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009;13(3):219-230.
3. Morphine sulfate package insert. Morgantown, WV: Mylan Pharmaceuticals Inc; 2014.4. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(suppl):S122-S153.
5. Koneru A, Satyanarayana S, Rizwan S. Endogenous opioids: their physiological role and receptors. Global J Pharmacol. 2009;3(3):149-153.
6. McNicholas L. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction: A Treatment Improvement Protocol (TIP) 40. Rockville, MD: U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment. DHHS Publication No. (SMA) 04-3939; 2004.
7. Spagnolo B, Calo G, Polgar WE, et al. Activities of mixed NOP and mu-opioid receptor ligands. Br J Pharmacol. 2008;153(3):609-619.
8. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth. 1985;57(2):192-196.
9. Buprenorphine. In: Martindale: The Complete Drug Reference [database online]. Greenwood Village, CO: Truven Health Analytics, Inc. Updated periodically. Accessed May 19, 2014.
10. Stolbach A, Hoffman RS. Opioid withdrawal in the emergency setting. In: Traub SJ, ed. UpToDate. Waltham, MA: UpToDate. Accessed September 8, 2014.
11. Dahan A. Opioid-induced respiratory effects: new data on buprenorphine. Palliat Med. 2006;20(suppl 1):s3-s8.12. De Maddalena C, Bellini M, Berra M, et al. Opioid-induced hypogonadism: why and how to treat it. Pain Physician. 2012;15(suppl):ES111-ES118.
13. Bliesener N, Albrecht S, Schwager A, et al. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. J Clin Endocrinol Metab. 2005;90:203-206.
14. Hallinan R, Byrne A, Agho K, et al. Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl. 2009;32(2):131-139.
15. Aurilio C, Ceccarelli I, Pota V, et al. Endocrine and behavioral effects of transdermal buprenorphine in pain-suffering women of different reproductive ages. Endocr J. 2011;58(12):1071-1078.
16. Steiner DJ, Sitar S, Wen W, et al. Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study. J Pain Symptom Manage. 2011;42(6):903-917.
17. Steiner D, Munera C, Hale M, et al. Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study. J Pain. 2011;12(11):1163-1173.
18. FDA. Extended-Release (ER) and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm311290.pdf. Accessed March 24, 2014.
19. Plosker GL, Lyseng-Williamson KA. Buprenorphine 5, 10 and 20 µg/h transdermal patch: a guide to its use in chronic non-malignant pain. CNS Drugs. 2012;26(4):367-373.
20. James IG, O’Brien CM, McDonald CJ. A randomized, double-blind, double-dummy comparison of the efficacy and tolerability of low-dose transdermal buprenorphine (BuTrans Seven-Day Patches) with buprenorphine sublingual tablets (Temgesic) in patients with osteoarthritis pain. J Pain Symptom Manage. 2010;40:266-278.
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