What is/are Buprenorphine?
Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2 mg), to control moderate acute pain in non-opioid-tolerant individuals in lower dosages (~200 µg), and to control moderate chronic pain in dosages ranging from 20–70 µg/hour. It is available in a variety of formulations: Subutex, Suboxone (buprenorphine HCl and naloxone HCl; 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).
Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, generally available as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/mL injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States also approved Suboxone and Subutex, buprenorphine's high-dose sublingual tablet preparations indicated for detoxification and long-term replacement therapy in opioid dependency, and the drug is now used predominantly for this purpose.
In the European Union, Suboxone and Subutex, buprenorphine's high-dose sublingual tablet preparations, were approved for opioid addiction treatment in September 2006. In the Netherlands, buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In the US, it was rescheduled to Schedule III drug from Schedule V just before FDA approval of Suboxone and Subutex. In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.
Depending on the application form, buprenorphine is indicated for the palliation of moderate to severe acute or chronic pain with no neuralgic component (or when the neuralgia is otherwise treated, such as with pregabalin), or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (which were released in the United States in January 2011, but were available in Australia and many European countries years beforehand) are preferred. The intravenous formulation is mainly used in postoperative pain (for example, as patient controlled analgesia [PCA]).
Sublingual buprenorphine (also sometimes taken buccally) for pain is available in the United Kingdom, as well as the Republic of India, in dosages of 200 and 400 µg. It is not available in the United States or in Canada, although Subutex or Suboxone (sublingual buprenorphine for addiction) is sometimes used off-label for this purpose, up to a dosage of 2 mg (the lowest-strength Subutex/Suboxone tablet). Sublingual formulations, such as Addnok, Temgesic, Subutex, and Suboxone, are used either as breakthrough medication for patients on transdermal treatment, or as monotherapy in cases where other treatments are not suitable. Niche pain indications for which sublingual/buccal buprenorphine may be a medication of choice include obstruction of the small bowel; continuous nasogastric suction; oesophageal fistula; malignancy in the head or neck; and other cases where the patient is unable to swallow or this is difficult. Additionally, this form of buprenorphine may be an interesting alternative to sustained-release opioids such as morphine (MS Contin) and oxycodone (Targin).
Advantages of buprenorphine in general in the treatment of chronic pain are, from a clinical perspective, its relatively long half-life, the option of sublingual and transdermal application and the excellent safety profile (ceiling effect for respiratory depression, lack of immunosuppressive effect, low pharmacokinetic interaction potential, no accumulation in renal impairment). Although not enough western literature is available, use of inj. buprenorphine in 'spinal' anaesthesia is rising in countries like India. Up to 150 micrograms of the drug (0.5 mL) of the preservative free solution is added to the local anaesthetic bupivacaine, and a smoother analgesia is obtained with the benefit of the patient remaining pain-free until up to eight to ten hours of the spinal being given.
Furthermore, buprenorphine is somewhat sleep-inducing, and may be of particular help when pain leads to sleeplessness. Other prototypical opioid side-effects may prove beneficial in the management of chronic pain, such as its characteristic euphoria (to alleviate depression due to pain, or in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants), as well as its anxiolytic effects. Buprenorphine is best used in opioid-naïve patients; its efficacy decreases dramatically with tolerance, and the high doses required in this situation, if combined with other opioids, may lead to opioid discontinuation syndrome.
Precipitated withdrawal and blockade effect
Use in persons physically dependent on full-agonist opioids while not already in withdrawal may trigger an extremely intense form of opioid withdrawal – called "precipitated withdrawal" or "precipitated withdrawal syndrome." This does not occur in all persons tolerant to full-agonist opioids, but rather depends on the severity of dependence and time elapsed from their last dose.
Buprenorphine (Subutex) itself binds more strongly to receptors in the brain than do other opioids, making it more difficult for opioids (or opiates) to react when buprenorphine is in the system. The blockade effect also has the result of blocking endogenous endorphins from binding to receptors, which can lead to psychological alterations in mood and mental capacity. This can cause cognitive and memory deficiencies via blockade of the reward system, which is pertinent to memory formation and normal mental function.
Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants in people not tolerant to either agent can cause fatal respiratory depression. Sedatives, hypnotics, and tranquilizers can be dangerous if ingested with buprenorphine by a person tolerant to neither opioids nor benzodiazepines. Co-intoxication with ethanol carries the greatest risk for lethal overdose, with the lowest doses of a reported fatality in a 48 kg teenage girl with 5 mg of diazepam and the equivalent of 8 ounces of beer (1 unit of alcohol), plus around 2 mg of buprenorphine. However, this female was tolerant to none of the three drugs she ingested that were the cause of the multiple drug intoxication fatality.
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, and urinary 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.
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, former doubts on 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 and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in prescribed doses, are not contraindicated in individuals tolerant to either opioids or benzodiazepines.
People on medium- to long-term maintenance with Suboxone or Subutex do not have a risk of overdose from buprenorphine alone, no matter what dosage is taken or route of administration it is taken by, due to the "ceiling effect" on respiratory depression. Overdoses occurring in maintenance patients are cases of multiple-drug intoxication, usually buprenorphine taken with excessive amounts of ethanol and/or benzodiazepine drugs. As a matter of course, all patients on buprenorphine maintenance are tolerant to opioids, and maintenance doses are always higher than the dose at which the "ceiling effect" on respiratory depression is reached (~3±1 milligrammes, depending on method of analysis).
People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can lead to the rapid onset of intense withdrawal symptoms, known as precipitated withdrawal. For short acting opioids such as codeine, hydrocodone, oxycodone, hydromorphone, pethidine, heroin, and morphine, 12–24 hours from the last dose is generally sufficient. For longer acting opioids such as methadone, 2–3 days from the last dose is needed to prevent precipitated withdrawal.
Switching from buprenorphine to other opioids is generally safe but requires careful dosing in the first few days. Initially, high doses of the alternate opioid are required to overcome buprenorphine's high receptor affinity. Over the next few days, these doses are reduced as buprenorphine's receptor blockade wears off. This issue is of particular relevance when the drug is used for analgesia: adequate levels of analgesia may be difficult or impossible to obtain without high (and potentially dangerous) levels of the alternate opioid.
Precipitated withdrawal can occur when an antagonist (or partial antagonist, such as buprenorphine) is administered to a patient dependent on full agonist opioids. Due to Buprenorphine's high affinity but low intrinsic activity at the mu receptor, it displaces agonist opioids from the mu receptors, without activating the receptor to an equivalent degree, resulting in a net decrease in agonist effect, thus precipitating a withdrawal syndrome.
It is a common misconception that the Naloxone in Suboxone initiates precipitated withdrawal. This is false. The Naloxone can only initiate precipitated withdrawal if injected into a person tolerant to opioids other than buprenorphine. Taken sublingually the Naloxone has virtually no effect. Even in injection scenarios Buprenorphine has a higher binding affinity for opioid receptors then even Naloxone, resulting in a fairly limited effect of the antagonist in any scenario.
Use in pregnancy
Unfortunately, due to the unique qualities of both methadone and buprenorphine, switching to and using buprenorphine during pregnancy instead of methadone is unlikely to be helpful, since the strain of withdrawal on the body is far more dangerous to the fetus than using a traditional opiate such as methadone. Data suggest that, after the first few weeks of life, no developmental differences are found between children born to mothers that were stable on an opiate during pregnancy versus those that were not taking opiates during pregnancy. Babies born to mothers addicted to opiates show signs of withdrawal if not addressed soon after birth This stands in stark contrast to the pathology seen after using the (otherwise socially acceptable) drug alcohol during pregnancy. It is notable that data regarding buprenorphine's safety during pregnancy is less available than is data on methadone use during pregnancy. There is a considerable body of evidence that proper methadone use during pregnancy is safe, and that there are few (if any) significant lasting effects on the children of mothers who use medically supervised methadone regimens during the gestation period. However, recent research has indicated methadone during pregnancy does indeed have a negative effect on the fetus, and needs to be followed up with further research to determine the full amount of damage done to the developing fetus by the methadone.
Detection in biological fluids
Buprenorphine and norbuprenorphine (the major active metabolite of buprenorphine) may be quantitated in blood or urine to monitor use or abuse, confirm a diagnosis of poisoning, or assist in a medicolegal investigation. There is a significant overlap of drug concentrations in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose. Therefore it is critical to have knowledge of both the route of administration of the drug and the level of tolerance to opioids of the individual when results are interpreted.
Buprenorphine is also used recreationally, typically by opioid users, often by insufflation. Recreational users of buprenorphine who crush the tablet and snort it report a euphoric rush similar to other opioids in addition to a slight "upper"-like effect. Those already using buprenorphine/Suboxone for opioid addiction therapy find that insufflation is only slightly, if any stronger than taking the pill sublingually, although it may have a quicker onset. Those taking it for addiction therapy also report that obtaining euphoria is virtually impossible after the first few doses, even when doubling or tripling their dosage. Many recreational users also report withdrawal symptoms. Due to the high potency of tablet forms of buprenorphine, only a small amount of the drug need be ingested to achieve the desired effects.
Recreational use of buprenorphine is very common in Scandinavia, especially in Finland and Sweden. In 2007, the authorities in Uppsala county in Sweden confiscated more buprenorphine than cocaine, ecstasy, and heroin. In Finland recreational use of buprenorphine is on the rise; in 2005, Finland's incidence of buprenorphine misuse (most often injected intravenously) surpassed the incidence of recreational usage of amphetamine.
Intravenous administration of dissolved buprenorphine pills and insufflation of pulverized pills are the most common modes of recreational buprenorphine use. This method of recreational use of Subutex is also seen in the Finnish documentary Reindeerspotting. The importer of legal Subutex to Sweden has in November 2012 stopped the sales of Subutex in Sweden due to problems with recreational use and drug induced deaths linked to Subutex.
Use in animals
In the United States and Canada, use of buprenorphine for pain management in animals has become increasingly common, and is a favored analgesic in feline patients for moderate to severe pain. Although registered only for human use by the Food and Drug Administration, it is legal for veterinarians to prescribe it for off-label use in animals they treat.
In the United Kingdom, buprenorphine is licensed for analgesia and sedation in dogs. A solution for injection is made available for the British veterinary market by Alstoe Animal Health under the trade name Vetergesic.
This article uses material from the Wikipedia article Buprenorphine, which is released under the Creative Commons Attribution-Share-Alike License 3.0.