It is a drug from the opioid group useful for the treatment of addiction to other opioids such as morphine and heroin in a similar way to methadone treatment . It was first marketed in the United States in the 1980s by Reckitt & Colman laboratories as a pain reliever , under the trade name Buprenex 0.3 mg / ml injectable. For the treatment of addiction to other opioids, the doses are usually much higher (> 2 mg) than those used as analgesic (> 200 µg).
Mechanism of action
Buprenoprfin is a potent µ-opioid receptor agonist. Opiate receptors include the µ (mu), (kappa), and (delta), all of them coupled to the receptors for the G protein and acting as modulators, both positive and negative, of the synaptic transmission that takes place through these proteins. . Opioid-protein C systems include cyclic-AMP and phospholipase-3C-inositol-1,4,5-triphosphate. Opioids do not alter the pain threshold of nerve endings afferent to nociceptive stimuli, nor do they affect the transmission of impulses along peripheral nerves.
Opioids also act as modulators of the endocrine and immune systems. Thus, they inhibit the release of vasopressin, somatostatin, insulin and glucagon, all due to the blockade of the neurotransmitters GABA and acetylcholine. It is not well understood how opioid agonists stimulate both stimulatory and inhibitory processes.
From a clinical point of view, stimulation of the receptors produces analgesia, euphoria, circulatory depression, decreased peristalsis, miosis, and dependence. The same effects are produced by the stimulation of the receptors, which also produce dysphoria and some psychomimetic effects (eg disorientation). Miosis is produced by an excitatory effect of the autonomic segment of the nucleus of the oculomotor nerve, while respiratory depression is due to a direct effect on the center that, in the brain, regulates respiration.
Opioid agonists increase muscle tone in the antral portion of the stomach, duodenum and large intestine, and sphincters. At the same time, they reduce gastric, pancreatic, and bile secretions, all of which results in constipation and delayed digestion. The tone of the urinary bladder also increases with opiate agonists, as well as that of the detrusor muscle, ureters and bladder sphincter, which can cause urinary retention. Other clinical effects that opioids can produce are cough suppression, hypotension, and nausea / vomiting. The antitussive effects of opioid agonists are due to a direct action on receptors in the cough center of the spinal cord and are achieved with doses lower than those necessary for analgesia. Hypotension is due to increased histamine release and depression of the vasomotor center of the medulla. Induction of nausea is the result of direct stimulation of the vestibular system.
Buprenorphine is a derivative of thebaine . Its analgesic effect is due to its partial agonist activity at μ- opioid receptors . (Rodríguez et al.) When a molecule binds to one of these receptors, it is only partially activated, unlike morphine, which is a full agonist. The high affinity of buprenorphine for μ-receptors is such that opioid antagonists for these receptors ( naloxone ) only partially reverses the effects.
These properties of this drug should be considered very carefully by the physician, since an overdose could not be easily reversed, although overdose is rare in addicted or opioid- tolerant patients . Its use in patients with physical dependence on full agonist opioids should also be taken into account, it could cause withdrawal syndrome , which would also be difficult to reverse and can last up to 24 hours.
It has an analgesic activity much higher than that of morphine (0.2 – 0.6 mg IM of buprenorphine, equivalent to 5 – 15 mg IM of morphine). The oral morphine versus transdermal buprenorphine comparison is 1: 110. (Sittl, R. et al.) In addition, its effect is longer. Respiratory depression is dose-dependent and equivalent to that of morphine. Buprenorphine is also an antagonist of κ- opioid receptors .
Buprenorphine is administered intramuscularly, intravenously, sublingually, and transdermally with the use of patches. It is metabolized by the liver. Its absorption is slow, with peak plasma concentrations being observed two hours after its administration. Sublingual tablets of this drug offer an analgesic effect for 6 to 8 hours. When higher doses are used to treat dependent patients, buprenorphine remains effective in the body between 24 and 48 hours, with cases of up to 72 hours.
Buprenorphine is indicated in the following cases:
- In the treatment of moderate or severe pain .
- As pre or post-operative analgesia.
- In the management of dependence on other opiates such as heroin .
The most frequently observed side effects are:
- Constipation .
- Headache .
- Insomnia .
- Asthenia .
- Drowsiness .
- Nausea and vomiting
- Lipothymia and vertigo .
- Hypotension .
- Sweating .
- Respiratory depression .
- Hallucinations .
The appearance of these manifestations will also depend on the type of patient and the level of tolerance with opioids.
Contraindications and precautions
Buprenorphine can cause respiratory depression, therefore it should be administered with caution in patients with respiratory failure. In patients under prolonged treatment with narcotic analgesics, or in addicts, its antagonistic properties can precipitate a moderate withdrawal syndrome, therefore it should be administered with caution in such cases.
Buprenorphine can cause mild drowsiness that could be enhanced by other centrally acting drugs. Therefore, patients should be advised to exercise caution when driving or operating dangerous machinery. Since buprenorphine is metabolized in the liver, the intensity and duration of its effect can be altered in patients with liver deficiencies.
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in people treated with buprenorphine in clinical trials. The spectrum of abnormalities ranges from asymptomatic and transient increases in liver transaminases to case reports of death, liver failure, liver necrosis, hepatorenal syndrome, and hepatic encephalopathy.
In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B virus or hepatitis C virus, concomitant use of other potentially hepatotoxic drugs, may have played a causal or contributory role. Withdrawal of buprenorphine has resulted in improvement of acute hepatitis in some cases; however, in other cases it was not necessary to reduce the dose.
Liver function tests are recommended before starting treatment, and regular monitoring of liver function is also recommended during treatment. Depending on the case, precautions should be taken to avoid withdrawal signs and symptoms and close monitoring of the patient should be initiated.
It should be used with caution in the elderly, with a history of congestive heart failure, intracranial lesions or convulsive states.
Safety in pregnancy has not been established and therefore its use in such states cannot be recommended. It should not be used as a pain reliever during labor. Do not use in pregnancy. Morphic derivatives are not teratogenic.
An abstinence syndrome has been described in the newborn, usually premature, of drug addicted mothers with behavioral disorders (hyperexcitability, hypertonia), insomnia, vomiting, diarrhea and hypersweating that can trigger a comatose state of fatal evolution.
Buprenorphine is classified in category C risk in pregnancy . At the moment, administration in children is not recommended.
Buprenorphine passes into breast milk. Breastfeeding is not recommended for mothers treated with this drug.
It should not be administered together with monoamine oxidase inhibitors and phenothiazines. Likewise, the consumption of alcohol and the use of other analgesics, sedatives or hypnotics should be avoided, since there is a risk of potentiating the central depressant action. In particular, its administration with tramadol should be avoided .
The possible interactions of buprenorphine with three classes of antiretroviral agents have been evaluated for their effects on CYP3A4. Nucleoside reverse transcriptase inhibitors do not appear to induce or inhibit the cytochrome P450 enzyme pathway, therefore, they do not cause interactions with buprenorphine. Non-nucleoside reverse transcriptase inhibitors are primarily metabolized by CYP3A4. Efavirenz, nevirapine, and etravirine are known inducers of CYP3A while delaviridine is an inhibitor of CYP3A. Significant pharmacokinetic interactions have been observed between non-nucleoside reverse transcriptase inhibitors (eg, efavirenz and delavirdine) and buprenorphine in clinical studies,
Some antiretroviral protease inhibitors with CYP3A4 inhibitory activity (nelfinavir, lopinavir / ritonavir, ritonavir) have little effect on the pharmacokinetics of buprenorphine and no significant pharmacodynamic effects.
Other protease inhibitors with CYP3A4 inhibitory activity (atazanavir and atazanavir / ritonavir) have resulted in elevated levels of buprenorphine and norbuprenorphine with increased sedation. Symptoms of opioid excess have also been observed in patients treated concomitantly with buprenorphine and atazanavir with and without ritonavir. Monitoring of these patients is recommended, and lowering the buprenorphine dose may be justified.
There have been a number of reports regarding coma and death associated with concomitant use of buprenorphine and benzodiazepines. In many, but not all, of these cases, buprenorphine was misused. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine alters buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Sublingual buprenorphine should be prescribed with caution in patients taking benzodiazepines or other drugs that act on the central nervous system, regardless of whether these drugs are prescribed by a doctor or are being misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines.
Athletes are informed that this medicine contains a component that can establish a doping control test result as positive.
Drowsiness may appear, easily reversible, especially in the postoperative period. Occasionally a slight euphoria has been observed. Respiratory depression, nausea, vomiting, dizziness, and sweating can occur in some outpatients. Sometimes slight variations in blood pressure and pulse have been detected, or difficulty in initiating urination. There is the possibility of withdrawal symptoms when discontinuing long-term treatment. If any other adverse reaction not described above is observed, consult your doctor or pharmacist.
Buprenorphine has a wide therapeutic margin and clinical experiences have shown that it is possible to administer doses much higher than those recommended without undesirable effects. If respiratory depression appears, the necessary measures must be taken to maintain adequate ventilation and oxygenation. It will be noted that naloxone only partially antagonizes the effects of buprenorphine. The use of doxapram, a nonspecific respiratory stimulant, administered intravenously at repeated doses or by infusion may be useful.
In the case of overdose, the primary treatment should be the restoration of adequate ventilation with mechanical assistance of respiration, if necessary. Naloxone may be of value for the treatment of buprenorphine overdose, but higher and repeated doses than normal doses may be necessary.The long duration of action of buprenorphine should be considered when determining the duration of treatment and monitoring necessary to reverse the effects of an overdose. Insufficient duration of monitoring can put patients at risk.
When its administration is interrupted, a suppression syndrome is generated, with a delay that varies from two days to two weeks; This syndrome consists of signs and symptoms similar to those of morphine withdrawal , but usually not very severe, and persists for 1 to 2 weeks.