Buprenorphine

Comparative studies

In patients undergoing long-term treatment for opiate addiction, there were only minor adverse events in those taking buprenorphine (17 of 106) or methadone (9 of 107) [ ]. The adverse effects included headache, constipation, somnolence, weakness, and insomnia with buprenorphine and weakness and constipation with methadone.

Placebo-controlled studies

In a randomized controlled trial the safety of buprenorphine for detoxification from opiates was highlighted [ ]. There were no withdrawals because of treatment-related adverse events.

Systematic reviews

A systematic review of the role of buprenorphine in the treatment of opioid dependence showed that it has therapeutic efficacy and a high safety profile, but is not necessarily suitable as a replacement to methadone [ ]. It is an additional treatment option for heroin-dependent patients, especially those who do not want to start or continue taking methadone, or for those who do not seem to benefit from optimal dosages of methadone [ ].

Cardiovascular

• A 27-year-old man injected a 2 mg suspension of crushed oral buprenorphine into his left ulnar artery, leading to acute ischemia of the hand; he was successfully treated with iloprost and dextran-40 [ ].

• A 22-year-old man snorted an 8 mg crushed tablet of buprenorphine and 2 hours later had crushing chest pain, which resolved within a few minutes [ ]. The symptom recurred 3 weeks later after another inhalation of buprenorphine. An electrocardiogram suggested an acute anterior myocardial infarction caused by buprenorphine-induced coronary artery spasm.

Respiratory

Respiratory depression can occur with buprenorphine. It is not often a clinical problem, except in older and weaker subjects, in whom it can be fatal [ ]. When it occurs it is often prolonged and can be particularly difficult to reverse [ ]. Norbuprenorphine, a metabolite of buprenorphine via CYP3A4 causes dose-dependent respiratory depression, perhaps mediated by opioid receptors in the lung rather than the brain, and is ten times more potent than buprenorphine [ ].

Buprenorphine showed a ceiling effect in its ability to cause respiratory depression in both rats and humans [ ]. There was a non-linear dose-response relation, due to partial MOR receptor agonism, between buprenorphine and respiratory effect.

Non-cardiogenic pulmonary edema has been reported after a single dose of buprenorphine [ ].

Nervous system

Sedation and nausea are relatively frequent. When buprenorphine is used for patient-controlled analgesia, minor dysphoria or euphoria has been reported [ ].

In one of three patients receiving epidural buprenorphine for the relief of pain from head and neck cancers, it was discontinued because of severe dizziness [ ].

Psychological

Buprenorphine caused significant deficits in cognitive and psychomotor functioning in 23 volunteers who were given 0.6 mg intravenously over 150 minutes and underwent neuropsychological tests of working memory, psychomotor function, concentration, sustained attention, vigilance, and information processing [ ]. There was significant impairment, and the time of onset was determined by slow distribution of the drug into the biophase.

Other effects have been found in other studies, particularly deficits in higher task-related activation of the frontal, parietal, and cerebellar regions, and reduced concentrations of N-acetylaspartate and glutamate/glutamine in the dorsal anterior cingulated cortex, which is believed to contribute to poor inhibitory control characteristic of addictive behavior [ ].

Psychiatric

In a comparison of buprenorphine and methadone in alleviating mood disturbances in conjunction with carbamazepine in 30 patients, buprenorphine was associated with better mood stabilization and short-term relief of depressive symptoms than methadone; both treatments were safe and without unexpected adverse effects [ ].

Mouth

There have been reports of facial and lingual ulcers, the ulceration following repeated injection of buprenorphine into the left superior cervical ganglion for trigeminal neuralgia [ ] and the use of sublingual buprenorphine [ ].

Gastrointestinal

Impaired gastric emptying and delayed absorption after sublingual buprenorphine have been reported [ ].

Buprenorphine has a low incidence of constipation compared with other opioids [ ].

Liver

Buprenorphine can cause increased liver enzymes at normal doses and at high doses can cause hepatitis [ ].

• A 33-year-old man developed severe hepatitis after an oral overdose of buprenorphine tablets 112 mg over 48 hours [ ]. He presented with an acute confusional state, including disorientation in time and the condition led to anuria and hepatorenal insufficiency. He was successfully treated with hemodialysis.

With increasing use of buprenorphine in the treatment of opioid dependence, it has been confirmed that the use of buprenorphine in opioid-dependent individuals with a history of hepatitis causes significant increases in aspartate transaminase and alanine transaminase activities [ ]. Liver enzymes should be monitored before giving buprenorphine to patients with hepatitis.

Four former opiate-dependent individuals with confirmed hepatitis C virus were given substitution therapy with sublingual buprenorphine. After injecting buprenorphine together with their sublingual doses, they had a marked increase in serum aspartate transaminase activity (13–50 times the upper limit of the reference range), resulting in jaundice [ ]. Another patient who was positive for hepatitis C and HIV developed jaundice, with panlobular liver necrosis and microvesicular steatosis, after using sublingual buprenorphine and small doses of paracetamol and aspirin [ ].

Intravenous buprenorphine abuse precipitated acute-on-chronic hepatitis in a 25-year-old woman who was hepatitis C positive with a history of chronic diamorphine dependence [ ].

Skin

There have been reports of severe pruritus with buprenorphine [ ].