Buprenorphine is a thebaine derivative that is legally classified as a narcotic. It is available in numerous countries for use as an analgesic. When used as an analgesic, Buprenorphine is usually given by injection, via a sublingual tablet, or as a transdermal patch, and doses are relatively low (compared with doses used in the treatment of opioid addiction). The typical analgesic dose of Buprenorphine is 0.30.6 mg (intramuscular or intravenous), and its analgesic effects last about 6 hours.
Buprenorphine is a partial agonist that exerts significant actions at the mu opioid receptor. As reviewed in the Thorough Technical Explanation of Buprenorphine section, however, its maximal opioid effects are less than that of full agonists, and reach a ceiling where higher doses do not result in increasing effect. Because it is a partial agonist, higher doses of Buprenorphine can be given with fewer adverse effects (e.g., respiratory depression) than are seen with higher doses of full agonist opioids. Past a certain point, dose increases of Buprenorphine do not further increase the pharmacological effects of the drug but do increase its duration of withdrawal suppression and opioid blockade.
At low doses, Buprenorphine is many times more potent than morphine. Individuals who are not dependent on opioids but who are familiar with the effects of opioids experience a subjectively positive opioid effect when they receive an acute dose of Buprenorphine. These subjective effects aid in maintaining compliance with Buprenorphine dosing in patients who are addicted to opioids.
Affinity, Intrinsic Activity, and Dissociation
Buprenorphine has high affinity for, but low intrinsic activity at, mu receptors. Buprenorphine displaces morphine, methadone, and other full opioid agonists from receptors. It also can block the effects of other opioids. Because of Buprenorphine's higher affinity for the mu receptor, full agonists cannot displace it and therefore will not exert an opioid effect on receptors already occupied by Buprenorphine. This effect is dose related, as shown in a study demonstrating that the 16-mg dose of the sublingual Buprenorphine-alone tablet was more effective than the 8-mg dose in blocking the reinforcing effects of heroin. Similarly, it is difficult for opioid antagonists (e.g., naloxone) to displace Buprenorphine and precipitate withdrawal.
Buprenorphine has a slow dissociation rate from the mu opioid receptor, which gives rise to its prolonged suppression of opioid withdrawal and blockade of exogenous opioids. This enables Buprenorphine dosing to occur on a less frequent basis than full opioid agonists. Buprenorphine can be given as infrequently as three times per week. The effectiveness of Buprenorphine as a medication for the treatment of opioid addiction on a daily or less-than-daily basis contrasts with its relatively short duration of action as an analgesic.
Buprenorphine has poor gastrointestinal (GI) bioavailability, and fair sublingual bioavailability. FDA-approved formulations of the drug for treatment of opioid addiction are in the form of sublingual tablets that are held under the tongue and absorbed through the sublingual mucosa. Studies of sublingually administered Buprenorphine have employed either an alcohol-based solution or a tablet formulation of the drug. Confusion may result when reviewing the literature on the effectiveness of Buprenorphine at various doses because most early trials and clinical studies of Buprenorphine were performed with a sublingually administered liquid preparation, whereas the oral formulations marketed in the United States are sublingual tablets. Studies have shown that the bioavailability of Buprenorphine in sublingual tablet form is significantly less than via sublingual liquid solution – about 5070 percent that of the liquid form, so the dosages of Buprenorphine sublingual tablets must be significantly higher than those used in the liquid form to achieve the same therapeutic effect.
Studies indicate that Buprenorphine is abusable. This is consistent with its action at the mu opioid receptor. The abuse potential, however, is lower in comparison with the abuse potential of full opioid agonists. This is consistent with Buprenorphine's partial agonist effects and the resultant ceiling in maximal effects produced. Still, abuse of the analgesic form of Buprenorphine through diversion to the injectable route has been reported internationally:
Abuse of Buprenorphine has been reported to occur via the sublingual and intranasal routes but primarily via diversion of sublingual tablets to the injection route. In a study from France, sublingual, Buprenorphine-only tablets (Subutex®), marketed for the treatment of opioid addiction, were diverted to the injection route.
Note: All of these diversion studies are for Subutex not Suboxone. Suboxone was created for the US market and contains Naloxone. The Naloxone will cause withdrawal in any opioid dependent misuser (intravenous misuse). In addition the Buprenorphine with its slow disassociation will block opiates for up to 72 hours. Limited evidence of Suboxone diversion is showing that when diverted the medication is not being misused but rather being used for its indication. The result is that the diversion is not causing harm or a danger to the public.
The primary side effects of Buprenorphine are similar to other mu opioid agonists (e.g., nausea, vomiting, constipation), but the intensity of these side effects may be less than that produced by full agonist opioids.
Buprenorphine Safety, Adverse Reactions, and Drug Interactions
Accidental Ingestion and Overdose
Because of the poor GI bioavailability of Buprenorphine, swallowing the tablets will result in a milder effect compared with administering them sublingually. (By extrapolation, Buprenorphine tablets are approximately one-fifth as potent when swallowed versus when taken sublingually.) The ceiling effect of Buprenorphine also adds to its safety in accidental or intentional overdose.
Preclinical studies suggest that high acute doses of Buprenorphine (analogous to an overdose) produce no significant respiratory depression or other life-threatening condition.
In contrast to full mu agonists, overdose of Buprenorphine (by itself) does not appear to cause lethal respiratory depression in healthy individuals. Buprenorphine, in combination with other sedative drugs, has been reported to produce respiratory depression.
Cognitive and Psychomotor Effects
Available evidence in patients maintained on Buprenorphine indicates no clinically significant disruption in cognitive and psychomotor performance.
Buprenorphine-Induced Precipitated Withdrawal
Administration of Buprenorphine can precipitate an opioid withdrawal syndrome. Although there is much variability in response to Buprenorphine, precipitated withdrawal symptoms tend to be milder than those produced by antagonist-precipitated withdrawal, and intervention is rarely required. In controlled studies in which Buprenorphine was given to individuals who were physically dependent on opioids, the precipitated withdrawal syndrome was both mild in intensity and easily tolerated. However, at least one open-label small-sample trial of low-dose Buprenorphine caused a patient to experience pronounced, precipitated, and poorly tolerated withdrawal of severe. The probability of precipitating a withdrawal syndrome is minimized by reducing the dose of mu agonist before Buprenorphine treatment is initiated, by allowing a longer elapsed interval between last agonist dose and first Buprenorphine dose, and by starting treatment with a lower Buprenorphine dose.
Benzodiazepines and Other Sedative Drugs
There have been case reports of deaths apparently associated with injections of Buprenorphine combined with benzodiazepines and/or other central nervous system (CNS) depressants (e.g., alcohol) It is prudent to assume that these cautions also should be applied to Buprenorphine combined with other CNS depressants, including alcohol and barbiturates.
Buprenorphine treatment should not be combined with opioid antagonists (e.g., naltrexone). It is common for individuals who are addicted to opioids to be concurrently dependent on alcohol. Although naltrexone may decrease the likelihood of relapse to drinking, patients maintained on opioids should not be given naltrexone to prevent alcohol relapse since the naltrexone can precipitate an opioid withdrawal syndrome in Buprenorphine-maintained patients.
Clinical situations may arise in which a full agonist may be required for patients who currently are being treated with Buprenorphine, such as in the treatment of acute pain. Although this medication interaction has not been studied systematically, the pharmacological characteristics of Buprenorphine suggest that it may be difficult to obtain adequate analgesia with full agonists in patients stabilized on maintenance Buprenorphine.
Data nonspecific to Buprenorphine suggests that, in patients maintained chronically on methadone, the acute administration of full mu agonists for analgesia can be effective. If the necessity should arise for the use of a full mu agonist for pain relief in a patient maintained on Buprenorphine, the Buprenorphine should be discontinued until the pain can be controlled without the use of opioid pain medications. It must be recognized that treatment with full mu agonists for pain relief will produce increased opioid tolerance and a higher degree of physical dependence.
Effectiveness of Buprenorphine Treatment
Buprenorphine can be used for either long-term maintenance or for medically supervised withdrawal (detoxification) from opioids. The preponderance of research evidence and clinical experience, however, indicates that opioid maintenance treatments have a much higher likelihood of long-term success than do any forms of withdrawal treatment. In any event, the immediate goals in starting Buprenorphine should be stabilization of the patient and abstinence from illicit opioids, rather than any arbitrary or predetermined schedule of withdrawal from the prescribed medication.
Results from studies suggest that Buprenorphine in a dose range of 816 mg a day sublingually is as clinically effective as approximately 60 mg a day of oral methadone, although it is unlikely to be as effective as full therapeutic doses of methadone (e.g., 120 mg per day) in patients requiring higher levels of full agonist activity for effective treatment.
The partial mu agonist properties of Buprenorphine make it mildly reinforcing, thus encouraging patient compliance with regular administration. This is in contrast to medications such as naltrexone, which also blocks the effects of opioid agonists but lacks any agonist effects. Because a medication such as naltrexone is not reinforcing, adherence in therapeutic use is poor. Naltrexone also may increase the risk for overdose death in the event of relapse following its discontinuation.
Medically Supervised Withdrawal
Although controlled clinical studies of the use of Buprenorphine as an agent for treating opioid withdrawal (detoxification) are scarce, some clinical research on its use for this indication has been conducted. In general, Buprenorphine has been used in three ways for withdrawal from opioids: long-period withdrawal (>30 days), usually on an outpatient basis; moderate-period withdrawal (>3 days but <30 days), again on an outpatient basis; and short-period withdrawal (<3 days), which often has been conducted on an inpatient basis. The available evidence from Buprenorphine and methadone research suggests that long-period Buprenorphine withdrawal probably would be more effective than moderate- or short-period withdrawals but that all forms of withdrawal are less effective compared with ongoing opioid maintenance
Although few data are available on the use of Buprenorphine for gradual withdrawal over a period of months, the literature on opioid withdrawal can be used to guide recommendations in this regard. This literature suggests that using Buprenorphine for gradual detoxification is more effective than its use for rapid detoxification in terms of patient compliance and relapse to opioid use. These findings are analogous to those seen with methadone which show that patients undergoing a 10-week methadone dose reduction (i.e., 10 percent per week) had a higher rate of opioid-positive urine samples than those receiving a 30-week dose reduction (i.e., 3 percent per week) and asked for more schedule interruptions.
Few studies of withdrawal from illicit opioids have been conducted using Buprenorphine for moderate periods (>3 days, but <30 days). Moderate-period withdrawal using Buprenorphine suppresses signs and symptoms of withdrawal, is tolerated by patients, and is safe. For example, a study comparing 10 days of Buprenorphine versus clonidine for the inpatient treatment of opioid withdrawal found Buprenorphine superior to clonidine in relieving withdrawal signs and symptoms.
The liquid form of Buprenorphine has been studied for the withdrawal from opioids over short periods (e.g., 3 days). In these studies, the doses of Buprenorphine administered were low (compared to maintenance doses) and typically were administered two or three times per day, either by injection or by having the patient hold the liquid under his or her tongue. (Note that this off-label use of the liquid form of Buprenorphine is unlawful outside an approved study setting and is now unnecessary due to the FDA approval of Subutex® and Suboxone®.)
The Buprenorphine/Naloxone Combination
There have been reports from several countries of abuse of Buprenorphine by injection. Because of this Buprenorphine abuse, a sublingual tablet form containing naloxone has been developed for the U.S. market to decrease the potential for abuse of the combination product via the injection route. Sublingual naloxone has relatively low bioavailability, while sublingual Buprenorphine has good bioavailability. (Both naloxone and Buprenorphine have poor GI bioavailability.) Thus, if a tablet containing Buprenorphine plus naloxone is taken as directed – sublingually – the patient will experience a predominant Buprenorphine effect. However, if an opioid-dependent individual dissolves and injects the combination tablet, then the antagonistic effect of naloxone predominates because of its high parenteral bioavailability. Under such circumstances, the individual should experience a precipitated withdrawal syndrome. This should decrease the likelihood of misuse and abuse of the combination tablet by the injection route.
The safety and efficacy profile of sublingual Buprenorphine/naloxone appears to be equivalent to that of Buprenorphine alone.
Buprenorphine has unique qualities that make it an effective and safe addition to the available pharmacological treatments for opioid addiction. The combination of Buprenorphine with the opioid antagonist naloxone further increases its safety and decreases – but does not eliminate – the likelihood of diversion and misuse.
To suppress the debilitating symptoms of cravings and withdrawal, enabling the patient to engage in therapy, counseling and support, so they can implement positive long-term changes in their lives which develops into the new healthy patterns of behavior necessary to achieve sustained addiction remission. - explain -