Accidental Ingestion And Overdose

Because of buprenorphine's poor GI bioavailability, 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.)Buprenorphine's ceiling effect 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 sequelae(e.g., circulatory collapse).Overdose of buprenorphine combined with other medications, however, may increase morbidity and mortality, as described further below.

Respiratory Depression

In contrast to full mu agonists, overdose of buprenorphine (by itself) does not appear to cause lethal respiratory depression in noncompromised individuals. Consistent with this clinical observation, a preclinical study of buprenorphine showed initial dose -related increases in pCO2 (arterial carbon dioxide level) followed by decreases in pCO2 compatible with buprenorphine's bell-shaped dose-response curve (Cowan et al. 1977). However, although none of the outpatient clinical trials comparing buprenorphine to methadone or placebo reported adverse events of respiratory depression, some cases have been reported of respiratory depression induced by buprenorphine in individuals not physically dependent on opioids (Gal 1989; Thörn et al. 1988). In addition, buprenorphine, in combination with other sedative drugs, has been reported to produce respiratory depression. (See "Drug Interactions" below.)

Cognitive and Psychomotor Effects

Available evidence in patients maintained on buprenorphine indicates no clinically significant disruption in cognitive and psychomotor performance (Walsh et al. 1994).

Hepatic  Effects

Elevation in liver enzymes (AST and ALT) has been reported in individuals receiving buprenorphine (Lange et al. 1990; Petry et al. 2000). There also appears to be a possible association between intravenous buprenorphine misuse and liver toxicity (Berson et al. 2001). See Johnson et al. (2003b) for further details. Mild elevations in liver enzymes have been noted in patients with hepatitis who received long-term buprenorphine dosing (Petry et al. 2000).

Perinatal Effects

There is limited clinical experience with buprenorphine maintenance in pregnant women who are addicted to opioids. The literature in this area is limited to case reports, prospective studies, and open-labeled controlled studies; however, norandomized controlled studies have been reported (Johnson et al. 2003b). See "Pregnant Women and Neonates"for a detailed discussion of the available clinical and research evidence.

Buprenorphine/Naloxone Combination

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 (Strain et al. 1995).

 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 intensity (Banys et al. 1994).

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.

Drug Interactions

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) (Reynaud et al. 1998a, b).Gaulier et al. (2000) reported a case of fatal overdose in which buprenorphine and its metabolites, as well as the metabolites of flunitrazepam, were very high at the time of death. Although it is not known if this is a pharmacodynamic interaction, Ibrahim et al. (2000) and Kilicarslan and Sellers (2000) suggest that, because of buprenorphine's weak ability to inhibit the cytochrome P450 3A4 system, the effect is more likely pharmacodynamic.

This interaction, however, underscores the importance for physicians to be cautious in prescribing buprenorphine in conjunction with benzodiazepines, as well as in prescribing buprenorphine to patients who are addicted to opioids and also are abusing or are addicted to benzodiazepines. It is prudent to assume that these cautions also should be applied to buprenorphine combined with other central nervous system depressants, including alcohol and barbiturates.

Opioid Antagonists

Buprenorphine 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. Thus, physicians should not prescribe naltrexone for patients being treated with buprenorphine for opioid addiction.

Medications Metabolized by Cytochrome P450 3A4

Buprenorphine is metabolized by the cytochrome P450 3A 4 enzyme system. Other medications that interact with this enzyme system should be used with caution in patients taking buprenorphine. No controlled studies, however, have examined these pharmacokinetic interactions. Figure 2-3 lists some of the drugs known to be metabolized by cytochrome P450 3A4. In some cases, these drugs may either enhance or decrease buprenorphine's effects  through actions on the cytochrome  P450 3A4 system.*

Partial List of Medications Metabolized by Cytochrome P450 3A4

Inhibitors (potentially increasing blood levels of buprenorphine)

Amiodarone  Clarithromycin  Delavirdine  Erythromycin Fluconazole  Fluoxetine  Fluvoxamine  Grapefruit Juice Indinavir  Itraconazole  Ketoconazole  Metronidazole Miconazole  Nefazadone  Nelfinavir Nicardipine Norfloxacin Omeprozol  Paroxetine  Ritonavir-S aquinavir  Sertraline Verapamil  Zafirlukast  Zileuton

Substrates

Alprazolam  Amlodipine  Astemizole  Atorvastatin Carbamazepine  Cisapride  Clindamycin  Clonazepam Cyclobenzaprine  Cyclosporine  Dapsone  Delavirdine Dexamethasone  Diazepam  Diltiazem  Disopyramide Doxorubicin  Erythromycin  Estrogen s Etoposide  Felodipine Fentanyl  Fexofenadine  Glyburide  Ifosfamide  Indinavir Ketoconazole Lansoprazole Lidocaine Loratadine Losartan Lovastatin  Miconazole  Midazolam  Navelbine  Nefazadone Nelfinavir  Nicardipine  Nifedipine  Nimodipine Ondansetron Oral Contraceptives  Paclitaxel  Prednisone  Progestins Quinidine  Rifampin  Ritonavir  R- Warfarin  Saquinavir Sertraline  Simvastatin  Tacrolimus  Tamoxifen  Verapamil Vinblastine  Zileuton

For a continuously updated list of cytochrome P450 3A4 drug interactions visit:   http://www.medicine.iupui.edu/flockhart/table.htm

      Opioid Agonists   

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 suggest 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. See "Patients With Pain" in  for a detailed discussion of the treatment of pain in patients maintained on buprenorphine.