FDA approves first buprenorphine implant for treatment of opioid dependence
Buprenorphine is a semisynthetic opioid derivative of thebaine. It is a mixed partial agonist opioid receptor modulator that is used to treat opioid addiction in higher dosages, to control moderate acute pain in non-opioid-tolerant individuals in lower dosages and to control moderate chronic pain in even smaller doses.[3] It is available in a variety of formulations: Cizdol,Subutex, Suboxone, Zubsolv, Bunavail (available as buprenorphine HCl alone or buprenorphine and naloxone HCl (seebuprenorphine/naloxone); typically used for opioid addiction), Temgesic (sublingual tablets for moderate to severe pain),Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan and Butrans (transdermal preparations used for chronic pain)
Pharmacokinetics[edit]
Buprenorphine is metabolised by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of buprenorphine is primarily carried out by UGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20–73 hours (mean 37). Due to the mainly hepatic elimination, there is no risk of accumulation in people with renal impairment.
One of the major active metabolites of buprenorphine is norbuprenorphine, which, contrary to buprenorphine itself, is a full agonist of the MOR, DOR, and ORL-1, and a partial agonist at the KOR.[59][60] However, relative to buprenorphine, norbuprenorphine has extremely little antinociceptive potency (1/50th that of buprenorphine), but markedly depresses respiration (10-fold more than buprenorphine).[61] This can be explained by very poor brain penetration of norbuprenorphine due to a high affinity of the compound for P-glycoprotein. In contrast to norbuprenorphine, buprenorphine and its glucuronide metabolites are negligibly transported by P-glycoprotein.[61]
The glucuronides of buprenorphine and norbuprenorphine are also biologically active, and represent major active metabolites of buprenorphine.Buprenorphine-3-glucuronide has affinity for the MOR (Ki = 4.9 pM), DOR (Ki = 270 nM) and ORL-1 (Ki = 36 µM), and no affinity for the KOR. It has a small antinociceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity for the MOR or DOR, but does bind to the KOR (Ki = 300 nM) and ORL-1 (Ki = 18 µM). It has a sedative effect but no effect on respiration.
Expanded use and availability of medication-assisted treatment is a top priority of federal effort to combat opioid epidemic
The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.
Until today, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person’s cheek until it dissolved. While effective, a pill or film may be lost, forgotten or stolen. However, as an implant, Probuphine provides a new treatment option for people in recovery who may value the unique benefits of a six-month implant compared to other forms of buprenorphine, such as the possibility of improved patient convenience from not needing to take medication on a daily basis. An independent FDA advisory committee supported the approval of Probuphine in a meeting held earlier this year.
“Opioid abuse and addiction have taken a devastating toll on American families. We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives,” said FDA Commissioner Robert M. Califf, M.D. “Today’s approval provides the first-ever implantable option to support patients’ efforts to maintain treatment as part of their overall recovery program.”
Expanding the use and availability of medication-assisted treatment (MAT) options like buprenorphine is an important component of the FDA’s opioid action plan and one of three top priorities for the U.S. Department of Health and Human Services’ Opioid Initiative aimed at reducing prescription opioid and heroin related overdose, death and dependence.
Opioid dependence is the diagnostic term used for the more common concept, “addiction,” in the Probuphine clinical trials. Addiction is defined as a cluster of behavioral, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence. Physical dependence is not the same as addiction. Newer diagnostic terminology uses the term “opioid use disorder,” which includes both milder forms of problematic opioid use as well as addiction.
MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use, without causing the cycle of highs and lows associated with opioid misuse or abuse. At sufficient doses, it also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their opioid use disorder cut their risk of death from all causes in half.
“Scientific evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more effective in the treatment of opioid use disorder than short-term detoxification programs aimed at abstinence,” said Nora Volkow, M.D., director of the National Institute on Drug Abuse at the National Institutes of Health. “This product will expand the treatment alternatives available to people suffering from an opioid use disorder.”
Probuphine should be used as part of a complete treatment program that includes counseling and psychosocial support. Probuphine consists of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm and provide treatment for six months. Administering Probuphine requires specific training because it must be surgically inserted and removed. Only a health care provider who has completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants. If further treatment is needed, new implants may be inserted in the opposite arm for one additional course of treatment. The FDA is requiring postmarketing studies to establish the safety and feasibility of placing the Probuphine implants for additional courses of treatment.
The safety and efficacy of Probuphine were demonstrated in a randomized clinical trial of adults who met the clinical criteria for opioid dependence and were considered stable after prior buprenorphine treatment. A response to MAT was measured by urine screening and self-reporting of illicit opioid use during the six month treatment period. Sixty-three percent of Probuphine-treated patients had no evidence of illicit opioid use throughout the six months of treatment – similar to the 64 percent of those who responded to sublingual (under the tongue) buprenorphine alone.
The most common side effects from treatment with Probuphine include implant-site pain, itching, and redness, as well as headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain. The safety and efficacy of Probuphine have not been established in children or adolescents less than 16 years of age. Clinical studies of Probuphine did not include participants over the age of 65.
Probuphine has a boxed warning that provides important safety information for health care professionals, including a warning that insertion and removal of Probuphine are associated with the risk of implant migration, protrusion, expulsion and nerve damage resulting from the procedure. Probuphine must be prescribed and dispensed according to the Probuphine REMS program because of the risks of surgical complications and because of the risks of accidental overdose, misuse and abuse if an implant comes out or protrudes from the skin. As part of this program, Probuphine can only be prescribed and dispensed by health care providers who are certified with the REMS program and have completed live training, among other requirements.
Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.
Probuphine is marketed by San Francisco-based Titan Pharmaceuticals Inc. and Braeburn Pharmaceuticals based in Princeton, New Jersey.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Adverse effects
Common adverse drug reactions associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, memory loss, cognitive and neural inhibition, perspiration, itchiness, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, andurinary retention. Constipation and CNS effects are seen less frequently than with morphine. Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.[citation needed]
Buprenorphine treatment carries the risk of causing psychological and or physical dependence. Buprenorphine has a slow onset, mild effect, and is very long acting with a half-life of 24 to 60 hours.[66]
Unlike methadone, long term use of buprenorphine does not significantly suppress plasma testosterone levels in men and is therefore less frequently related to sexual side effects.[67]
The most severe and serious adverse reaction associated with opioid use in general is respiratory depression, the mechanism behind fatal overdose. Buprenorphine behaves differently than other opioids in this respect, as it shows a ceiling effect for respiratory depression. Moreover, doubts about the antagonisation of the respiratory effects by naloxone have been disproved: Buprenorphine effects can be antagonised with a continuous infusion of naloxone.Concurrent use of buprenorphine with other CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in recommended doses, are not contraindicated in individuals tolerant to either opioids or benzodiazepines.
There is another consequence of high-dose buprenorphine treatment that often goes overlooked by both physicians and patients when electing to use buprenorphine (in the form of Butrans transdermal patches) for chronic pain management. Because buprenorphine binds so tightly to μ‑opioid receptors in the central nervous system, it takes an extremely large dose of potent opioid pain medication to displace the buprenorphine from those receptors and provide additional pain relief in the acute setting. Patients on high-dose buprenorphine therapy may be unaffected by even very large doses of potent opioids such as fentanyl, morphine, or hydromorphone. Sufentanil (trade name Sufenta) is an extremely potent opioid analgesic (5 to 10 times more potent than fentanyl and 500 times more potent than morphine) for use in specific surgeries and surgery in highly opioid-tolerant or opioid-dependent patients that has a binding affinity that is high enough to theoretically break through a “buprenorphine blockade” to provide pain relief in patients taking high-dose buprenorphine. The problem is that sufentanil is frequently not available in the emergency room or acute care setting because of its highly specialized indications, thus making it very problematic for acute care practitioners to manage severe acute pain in persons already taking high-dose buprenorphine. It is also difficult to achieve acute opioid analgesia in persons using buprenorphine for opioid replacement therapy. Here, fentanyl, which has a higher affinity for μ‑opioid receptors, can successfully overcome buprenorphine blockade. Fentanyl is widely available in acute care settings
