Introduction to Buprenorphine

Buprenorphine is a semi-synthetic, partial opioid agonist derived from thebaine; a natural alkaloid of the opium poppy. It has partial agonist actions at the mu opioid receptor and antagonist actions at the kappa opioid receptor. This mechanism of action means that although buprenorphine is an opioid, and thus can produce typical opioid agonist effects and side-effects such as euphoria and respiratory depression, its maximum effects are less than those of full agonists like heroin and methadone. At low doses buprenorphine produces sufficient agonist effects to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms.

Buprenorphine hydrochloride was first marketed in the 1980s by pharmaceutical manufacturers Reckitt Benckiser (formally Reckitt & Colman) as an analgesic and in 2002 the Food & Drug Administration (FDA) in the United States approved 'Suboxone' and 'Subutex'- buprenorphine's high-dose sublingual preparations for the treatment of opioid addiction. Subutex & Suboxone are now primarily used for this purpose.

2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5 epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3 dimethylbutan-2-ol
Chemical Structure of Buprenorphine

Using Buprenorphine

Buprenorphine hydrochloride is administered by intramuscular (I.M) injection, intravenous (I.V) infusion, via a transdermal patch, as a sublingual tablet or an ethanolic liquid oral solution. Due to it's high first-pass metabolism, via CYP3A4, it is not consumed orally..

Buprenorphine versus methadone

Buprenorphine has the advantage of being a partial agonist; hence negating the potential for life-threatening respiratory depression in cases of abuse. Studies show the effectiveness of buprenorphine and methadone are almost identical, along with the statistical likeliness of any adverse effects except for more sedation among methadone users. At low doses from 2 to 6 mg, however, Suboxone has a lower retention rate than low doses from 40 mg or less of methadone.

Ways of administration

Buprenorphine can be use sublingually for opiate detox/maintenance. It can be use I.V. and I.M. in a hospital setting and it can be prescribed in transdermal patches for pain.

Transdermal patches deliver their Buprenorphine 35, 52.5 and 70 mcg per hour for a total of 3 day. Transdermal use of buprenorphine is used as a measure of pain-control

Sublingual use of Buprenorphine

Both Suboxone and Subutex are meant for sublingual use only (placing the pill under ones tongue until it dissolves. Buprenorphine has a ceiling effect at 32mg.

Effects of Buprenorphine

Full opioid agonists attach to receptors in the brain (specifically the mu receptor), with three main effects; reduced respiration, euphoria, and decreased pain. The more opioids that are ingested, the more they produce an effect. This process of opioids binding to the opioid receptors can be thought of as a mechanical union. The better the fit, the greater the opioid effect.

Buprenorphine is a partial agonist, and thus its mode of action is slightly different. It too binds to the opioid receptors, however, it does so without having a perfect fit. As a result, the Buprenorphine will still occupy the receptors, but it does so without producing all of the opioid effects. The receptor is tricked into thinking it has been satisfied with opioids without producing strong feelings of euphoria, and without causing significant respiratory depression. This, in turn, prevents that receptor from joining with full opioids; therefore if the patient uses heroin or opioid pain medications, they are unlikely to experience any additional effects.

Buprenorphine tends to firmly attach and stay with the receptors, blocking them much longer then full agonists opioids do. This stickiness (affinity), is what gives buprenorphine its ability to block opioid full agonists, as well as its relatively long half-life.

The agonist effects of buprenorphine increase linearly with increasing doses of the drug, until at moderate doses, where they reach a plateau and no longer continue to increase with further dosing. This is called the "ceiling effect". Thus, buprenorphine carries a lower risk of abuse, addiction, and side effects compared to full opioid agonists. In fact, at high doses and under certain circumstances, buprenorphine can actually block the effects of full opioid agonists and can precipitate withdrawal symptoms if administered to an opioid-addicted individual while a full agonist is in the bloodstream.

Buprenorphine has poor oral bioavailability and moderate sublingual bioavailability. Formulations for opioid addiction treatment are in the forms of sublingual tablets and a solution for IM injection. The half-life of buprenorphine is 24–60 hours.

Side effects of Buprenorphine

Side effects of buprenorphine are similar to those of other opioids or full-agonist opiates and include:

chills
constipation
diarrhea
dizziness
flushing
headache
nausea
sleeplessness
stomach pain
vomiting
decreased interest in sex
decreased ability to perform sexually,
miosis (pin point pupils)

Buprenorphine treatment must not be ceased without a gradual taper/reduction in dose or the individual will experience withdrawals which can last up to a couple weeks. The prescribing doctor will advise patients on how best to taper the treatment and avoid discomfort.

Combinations with Buprenorphine

Buprenorphine is commonly combined with Naloxone in various different opioid maintanence medications. Naloxone is an opioid antagonist but is inactive unless taken intravenously or intramuscularly. The combination with Naloxone prevents users from injecting the medication. Injection of Naloxone containing Buprenorphine products will result in either zero opiate like effects or instant precipitated withdrawals, depending on whether or not your receptors are already saturated with opiate/opioids. Although, some people claim to inject Naloxone containing Buprenorphine products without any problems.

Combining buprenorphine with Central Nervous System(CNS) depressants like sedatives, hypnotics or tranquilers can be dangerous. This especially includes benzodiazepines, alcohol, and other opioids.

Different Uses for Buprenorphine

It is used for opiate and opiate maintenance as well as pain relief.

Using Buprenorphine to counter opiate withdrawals

There is no conclusive evidence of an optimal buprenorphine dosing regime for heroin (or other short acting opioids) withdrawal. In general, daily buprenorphine doses of 4 to 16 mg appear to be most effective in reducing withdrawal severity and continued opioid use.

Induction onto buprenorphine for the purposes of detoxification should follow the same principles as buprenorphine maintenance. Reductions in the buprenorphine dose should not be commenced until the patient has received a dose that virtually abolishes withdrawal symptoms for 24 hours. Some flexibility in dosing is allowable to accommodate a range of factors; such as amount of heroin used and a patients psychological condition. All of which may have an impact on each patient’s individual dosing requirements and withdrawal severity.

Review by a trained health professional is recommended on a daily basis during the first few days of the withdrawal regime. This is important so that doses can be adjusted if necessary, and any difficulties being experienced from the medication can be addressed. It is also needed to ensure provision of appropriate support, care, and monitoring.

Doctors may choose to prescribe a fixed daily dose (e.g. Day 1: 6 mg, Day 2: 8 mg, Day 3: 10 mg, Day 4: Begin titration, etc) or, alternatively, prescribe a flexible regime with upper and lower limits on any particular day along with instructions for the pharmacist or withdrawal worker regarding dose titration (e.g. Day 1: 6 mg, Day 2: 6–10 mg, Day 3: 8–12 mg, etc).

The planned duration of withdrawal treatment should be guided by the patient. Most commonly the duration of buprenorphine administration will be between five and 20 days.

Long-term reduction regimes (over 2 to 3 weeks) permit more time for relapse prevention and after-care planning, but there are good reasons for preferring a short-term withdrawal regime (4 to 5 days) and not unnecessarily prolonging buprenorphine treatment.

The administration of buprenorphine for more than several days may be associated with rebound withdrawal when ceased. Such rebound withdrawal typically starts one to three days after the last dose of buprenorphine and peaks two to five days after the last dose. Some symptoms may even persist for several weeks.

Ideal candidates for opioid addiction maintenance therapy with buprenorphine are:

- Individuals who have been objectively diagnosed with opioid addiction.
- Are willing to follow safety precautions for treatment.
- Can be expected to fully comply with the treatment.
- Have no contraindications to buprenorphine therapy.
- And who agree to buprenorphine treatment after a review of all other possible treatment options.

Starting Buprenorphine Maintenance Therapy.

There are three phases of buprenorphine maintenance therapy. These phases are; induction, stabilization, and maintenance.

1: The induction phase:

This phase is the medically monitored start up of buprenorphine therapy. Buprenorphine induction therapy is initiated when an opioid-addicted individual has abstained from using opioids for 12–24 hours and is in the early stages of opioid withdrawal. If the patient is not in the early stages of withdrawal (i.e., if he or she has other opioids in the bloodstream), then the buprenorphine dose could precipitate acute withdrawal.

Because buprenorphine is a partial mu-opioid agonist with a maximal effect less than that of a full mu-opioid agonist (eg, morphine, methadone, or heroin), the induction regimen can be more aggressive. The risk of serious adverse effects such as an overdose or treatment dropout is greater if a patient is under treated with buprenorphine and continues to self-medicate withdrawal symptoms with other opioids, alcohol, sedative-hypnotics, or benzodiazepines.

Preventing buprenorphine precipitated withdrawal.

Buprenorphine can precipitate opioid withdrawal in someone who has recently used heroin (within the past 6 hours), slow-release oral morphine (within the past 12 hours) or higher doses of methadone (within 36 hours). Buprenorphine precipitated withdrawal typically commences one to four hours after the first buprenorphine dose, is generally mild to moderate in severity, and lasts for up to 12 hours. Patients experiencing severe discomfort may benefit from symptomatic withdrawal medications (e.g. clonidine, ibuprofen, & loperamide), and should be directed to see their prescribing doctor.

Patients should not receive the first dose of buprenorphine if they are still experiencing the effects of short acting opioids. It is preferable to withhold the first dose until the patient is beginning to experience the early signs of withdrawal. Typically this will occur six hours or more after their last use of opioids like heroin. If there are doubts or concerns, the patient should hold off on dosing until later in the day, or alternatively, a lower initial dose can be dispensed (e.g. 2 or 4 mg) as it is less likely to precipitate significant withdrawal than a high initial dose.

Since buprenorphine has a higher binding strength at the opioid receptor, it will compete for that receptor. In other words, buprenorphine kicks off and replaces existing opioids at the receptor site. If a significant amount of opioids are expelled from the receptors and then replaced, the opioid physically dependent person will feel the rapid loss of the opioid effect, which in turn will initiate withdrawal symptoms.

To avoid precipitated withdrawal, physically dependent patients must no longer be experiencing the agonist effects of an opioid. One way to gage this is to observe objective symptoms of withdrawal sufficient to score a minimum of 5 to 6 on the COWS (Clinical Opioid Withdrawal Scale). Scores of >10 are preferable, but due to patient individuality, required abstinent times may vary considerably from patient to patient. Only use the time since last use as an estimate to anticipate the onset of withdrawal symptoms.

The complete COWS can be viewed here: Clinical Opioid Withdrawal Scale (COWS)

2: The stabilization phase:

This phase has begun when a patient has discontinued or greatly reduced the use of his or her drug of abuse, no longer has cravings, and is experiencing few or no side effects. The buprenorphine dose may need to be adjusted during the stabilization phase in order to achieve this. Because of the long half-life of buprenorphine, it is sometimes possible to switch patients to alternate-day dosing once stabilization has been achieved.

3: The maintenance phase:

This phase is reached when the patient is doing well on a steady dose of buprenorphine (or buprenorphine/naloxone). The length of time of the maintenance phase is individualized for each patient and may be indefinite if one so chooses. The alternative to going into (or continuing) a maintenance phase once stabilization has been achieved, is medically supervised withdrawal.

Recreational use of Buprenorphine

Buprenorphine can be used recreationally, typically by opioid (opioid naive) users, as abuse by those who have opiates in their system already would cause precipitated withdrawal. Recreational users of Suboxone who crush the tablet and inhale it through their nose report intense feelings of euphoria similar to that of cocaine and ecstasy. Opioid tolerant users find obtaining euphoria virtually impossible. Many recreational users also report withdrawal symptoms.

Pharmacology of Buprenorphine

Buprenorphine has been reported to possess the following pharmacological activity:

μ-Opioid receptor (MOR): Partial agonist. Binds with high affinity, but only partially activates the receptor. This property allows buprenorphine to act similarly to full opioid agonists at lower doses (mainly in non-tolerant individuals), reaching a ceiling/plateau at higher doses after which there is no further increase in typical opioid effects (therapeutic or recreational). This behavior is responsible for buprenorphine's ability to block most MOR agonists and the phenomenon of precipitated withdrawal when used in actively opioid dependent persons.
κ-Opioid receptor (KOR): Antagonist.
δ-Opioid receptor (DOR): Antagonist.
Nociceptin receptor (NOP, ORL-1): Weak affinity. Very weak partial agonist. May be involved in lack of respiratory depression with buprenorphine in overdose.
In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist–antagonist opioid receptor modulator, acting as a weak partial agonist of the MOR, an antagonist of the KOR, an antagonist of the DOR, and a relatively low-affinity, very weak partial agonist of the ORL-1.

Although buprenorphine is a partial agonist of the MOR, human studies have found that it acts like a full agonist with respect to analgesia in non-opioid-tolerant individuals. Conversely, buprenorphine behaves like a partial agonist of the MOR with respect to respiratory depression.

Buprenorphine is also known to bind to with high affinity and antagonize the putative ε-opioid receptor.

Chemistry of Buprenorphine

Column 1	Column 2
Systematic (IUPAC) name:	(2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Synonyms:	(αS,5α,7α)-17-(cyclopropylmethyl)-α-(1,1-dimetylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenemorphinan-7-methanol, 21-cyclopropyl-7α-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine, 21-cyclopropyl-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine, RX-6029-M; CL-112302, NIH-8805, UM-952, Buprenex, Lepetan, Subutex, Temgesic (hydrochloride)
Molecular Formula:	C29H41NO4, C29H41NO4.HCl
Molar mass:	467.65 g/mol, 504.11 g/mol (hydrochloride)
CAS Registry Number:	52485-79-7, 53152-21-9 (hydrochloride)
Melting Point:	209°C
Boiling Point:	no data
Flash Point:	no data
Solubility:	Hydrochloride : low solubility in water, high solubility in oils
Additionnal data:	none
Notes:	Freebase aspect crystals. Hydrochloride aspect : white powder; highly lipophilic

[1]

The Dangers of Buprenorphine

Overdose caused by buprenorphine itself is rare, due to its ceiling dose & blockade effects, however a combination with other CNS depressants, such as barbiturates or benzodiazepines should be avoided.

Buprenorphine Overdose

Overdose from buprenorphine is rare because its both a partial agonist and antagonist and it has a ceiling effect at 32mg. However overdoses have and can happen especially when used in conjunction with other CNS depressants such as alcohol, benzodiazepines, barbiturates, z-drugs, GHB, and any other substance that depresses the central nervous system.

Because of its ceiling effect and poor bioavailability, buprenorphine is safer in overdose than full opioid agonists. The maximal effects of buprenorphine appear to occur in the 16–32 mg dose range for sublingual tablets. Higher doses are unlikely to produce greater effects, and respiratory depression from buprenorphine (or buprenorphine/naloxone) overdose is less likely than from other opioids. There is no evidence of organ damage with chronic use of buprenorphine, although increases in liver enzymes are sometimes seen. Likewise, there is no evidence of significant disruption of cognitive or psychomotor performance with buprenorphine maintenance dosing.

Producing Buprenorphine

Buprenorphine is synthetized from thebaïne according to the following scheme. [2]

Forms of Buprenorphine

Buprenorphine is now commonly prescribed under the brand names Suboxone, Subutex, Zubzolv and Butrans.
There is also a generic version of Suboxone produced by two different pharm companies.(as of 3/01/2013)

Suboxone comes in three different forms. The first is an uncoated hexagonal orange tablet, and the second is a rectangular shaped film, the third is in generic un-coated white round tablets. All of which are intended for sublingual administration. The suboxone tablet is available in two dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, and 8 mg buprenorphine with 2 mg naloxone free bases.

Suboxone film now also comes in 12mg Buprenorphine with 3mg Naloxone strength strips,

Subutex is an uncoated oval white tablet or a round un-coated white pill intended for sublingual administration. It is available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine free base.

Zubsolv comes as an uncoated white round tablet as well as an uncoated white triangular tablet both for sublingual administration, both of different dosage strengths. The uncoated white round tablet has 5.7mg of Buprenorphine and 1.4mg of Naloxone. The uncoated white triangular tablet has 1.4mg of Buprenorphine and .36mg of Naloxone. Zublov is said to absorb better than Suboxone or Subutex, hense the smaller dosages.

Butrans is a transdermal patch used for managing moderate to servere chronic pain. Butrans helps in cases when an opioid analgesic is need around the clock and for an extended period of time. Butrans patches comes in dosage strengths of 5, 10, 15, or 20mcg per hour over a 7 day period.

Legal status of Buprenorphine

Buprenorphine is a controlled substance 21 CFR 1308.13

United Nations

USA

In 2002 the FDA approved buprenorphine for use in opiate detox and opiate substitution therapy (maintenance) and the United States congress passed special legislation which allows the drug, to be dispensed by private doctors who undergo a special training course, under the brand names Subutex (which is pure buprenorphine) and Suboxone (which is mixed with the opiate antagonist naloxone, its 1 part naloxone for every 4 parts buprenorphine), the purpose of Suboxone was to deter abuse

EU

Buprenorphine was first marketed in the United States in 1985 as a schedule V narcotic analgesic. Initially, the only available buprenorphine product in the United States had been a low-dose (0.3 mg/ml) injectable formulation under the brand name, Buprenex®. Diversion, trafficking and abuse of other buprenorphine products have occurred in Europe and other areas of the world. In October 2002, the Food and Drug Administration (FDA) approved two buprenorphine products (Suboxone® and Subutex®) for the treatment of narcotic addiction. Both products are high dose (2 mg and 8 mg) sublingual (under the tongue) tablets: Subutex® is a single entity buprenorphine product and Suboxone® is a combination product with buprenorphine and naloxone in a 4:1 ratio, respectively. After reviewing the available data and receiving a schedule III recommendation from the Department of Health and Human Services (DHHS), the DEA placed buprenorphine and all products containing buprenorphine into schedule III in 2002. Since 2003, diversion, trafficking and abuse of buprenorphine have become more common in the United States. In June 2010, FDA approved an extended release transdermal film containing buprenorphine (Butrans®) for the management of moderate to severe chronic pain in patients requiring a continuous, extended period, around-the-clock opioid analgesic

History of Buprenorphine

In the 1980s it was introduced under the brand names Temgesic and Buprenex. It was used for their analgesic properties.

In 2002 the FDA approved buprenorphine for use in opiate detox and opiate substitution therapy (maintenance). The United States congress passed special legislation which allows the drug to be dispensed by private doctors who undergo a special training course. Under the brand names Subutex (which is pure buprenorphine) and Suboxone (which is mixed with the opiate antagonist naloxone, its 1 part naloxone for every 4 parts buprenorphine), the purpose of Suboxone was to deter abuse. However, before this in the 1980's, buprenorphine was legalized for use as a pain killer.

More Buprenorphine Sections

Buprenorphine forum
Buprenorphine images
Buprenorphine Studies

References

1. ^Merck Index, fifteenth edition (2013)
2. ^Synthesis of Essential Drugs, 1st edition, Ruben Vardanyan & Victor Hruby, Elsevier

-Clinical Opioid Withdrawal Scale
-Effects of Buprenorphine and Methadone in Methadone-Maintained Subjects Walsh SL, June HL, Schuh KJ, Preston KL, Bigelow GE, Stitzer ML.
-Gowing et al. 2006
-National Alliance of Advocates for Buprenorphine Treatment
-National (U.S.) clinical guidelines and procedures for the use of buprenorphine in the Maintenance Treatment of Opioid Dependence
-Physicians Desk Reference (2009)
-Substance Abuse & Mental Health Services Administration (samhsa.gov)
-The National Center for Biotechnology Information (NCBI)
-U.S. National Health Information Center (Health.gov)