Buprenorphine

Also known as

Subuxone, subbies, temgesic, temmies, tems, subutex, subs, bupe, bup, B

Classification

Depressant, analgesic, opioid

Overview

Buprenorphine is an opioid analgesic or pain killer used in the treatment of moderate to severe pain. It is also licensed for use as a substitute for heroin or morphine and is prescribed to people wanting to come off these drugs. It is different from other opioids in that it is a partial opioid agonist. This means that there is less euphoria and physical dependence and a relatively mild withdrawal syndrome .

The aim of buprenorphine treatment is to -

• suppress symptoms of opioid withdrawal,
• decrease cravings for opioids and hence illicit opioid use,
• block some of the effects of other opioids,
• change risky behaviour such as injecting and sharing needles,
• stop the need to commit crimes to fund the heroin habit,
• help patients stay in treatment .

Trade names for buprenorphine include, Subutex, Suboxone and Temgesic. Subutex comes in tablet form and these are usually taken orally - dissolved under the tongue .

Medical usage

To treat moderate to severe chronic pain, treatment of opiate addiction . For the treatment of moderate to severe pain, peri-operative analgesia, and opioid dependence .

Source

Semi-synthetic opiate that acts on opiate receptors in the brain and also blocks them. Diverted from manufacturers, pharmacies, GP's prescriptions .

Street price

The street prices for 'Buprenorphine tablets by Sandoz, 8mg pill' are currently £10. Subutex tablets, 8mg, range between £1 to £10 .

Why take it?

Sought after effects

• euphoria,
• reduced anxiety,
• relaxation .

Undesired effects

• drowsiness,
• confusion,
• disorientation .

Dosage

Abuse

Insufflated

• threshold < 0.2 mg,
• light 0.2 - 0.4 mg,
• common 0.4 - 0.8 mg,
• strong 0.8 - 1.5 mg,
• heavy 1.5 mg + .

Sublingual

• threshold <0.3 mg,
• light 0.3 - 0.6 mg,
• common 0.6 - 1.3 mg,
• strong 1.3 - 2.4 mg,
• heavy 2.4 mg + .

What are the different forms?

Orally or injection. Tablets may be crushed and injected .

How long do its effects last?

Onset of effects

• insufflated - 30 - 60 minutes,
• sublingual - 40 - 80 minutes , 30 - 60 minutes .
• all ROA's - 60 - 90 minutes .

Peak

• insufflated - 4 - 8 hours,
• sublingual - 4 - 8 hours , 1 - 4 hours .

Duration of effects

• insufflated - 8 - 14 hours,
• sublingual - 10 - 18 hours .
• all ROA's - low hours ,
• insufflated (low dose) - 8 - 12 hours,
• insufflated (high dose) - 24 - 72 hours .

After-effects

• insufflated - 1 - 3 days,
• sublingual - 1 - 3 days ,
• all ROA's - 1 - 16 hours .

Pharmacology

Buprenorphine exerts its effects by binding to and activating the μ-opioid receptor. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement .

Buprenorphine is a derivative of the opioid alkaloid thebaine that is a more potent (25 - 40 times) and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use .

Pharmacodynamics

Buprenorphine is a synthetic opioid analgesic and thebaine derivative, with a longer duration of action than morphine. Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the CNS. Its primary actions of therapeutic value are analgesia and sedation. Buprenorphine may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Pharmacological effects peaks at 15 minutes and persists for 6 hours or longer when given intramuscularly. When given intravenously, the time to onset and peak effect are shortened .

Absorption

31% bioavailability (sublingual). Sublingual absorption is also dependent on pH. The length of time the tablet is under the tongue has little effect on absorption. Although buprenorphine is rapidly absorbed from the oral mucosa, the absorption into the systemic is slower. The time to reach peak plasma concentration (Tmax) varies between individuals (range of 40 minutes to 3.5 hours). How buprenorphine is formulated does not affect this pharmacokinetic parameter. It also undergoes extensive first-pass metabolism and as a consequence, has very low oral bioavailability. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine .

Bioavailability

• oral 22%,
• sublingual 30%,
• intramuscular 90% - 100% .

Metabolism

Hepatic. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by cytochrome P-450 3A4 isozyme. Norbuprenorphine, an active metabolite and has one-fifth of the pharmacologic activity of the parent compound, can further undergo glucuronidation .

Half-life

IV administration, 0.3 mg = 1.2 - 7.2 hours (mean 2.2 hours); Sublingual administration = 37 hours .

Elimination

Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolised by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via faeces (as free forms of buprenorphine and norbuprenorphine) while 10% - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine) .

Lethal dosage

LD50 in rats 3.1511 mol/kg .

Tolerance

Tolerance to many of the effects of buprenorphine develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Buprenorphine presents cross-tolerance with all other opioids, meaning that after the consumption of buprenorphine all opioids will have a reduced effect .

Mechanism of action

Buprenorphine's analgesic effect is due to partial agonist activity at mu-opioid receptors. Buprenorphine is also a kappa-opioid receptor antagonist. The partial agonist activity means that opioid receptor antagonists (e.g., an antidote such as naloxone) only partially reverse the effects of buprenorphine. The binding to the mu and kappa receptors results in hyperpolarization and reduced neuronal excitability. Furthermore, buprenorphine slowly dissociates from its receptor. This observation would account for the longer duration of action compared to morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence. Its receptor fixation half life is 40 minutes which is significantly longer than morphine (milliseconds) .

Effects

Physical effects

• physical euphoria,
• pupil constriction,
• appetite suppression,
• cough suppression,
• orgasm suppression,
• pain relief,
• respiratory depression,
• sedation,
• constipation,
• decreased heart rate,
• difficulty urinating,
• dizziness,
• itchiness,
• nausea .

Cognitive effects

• cognitive euphoria,
• anxiety suppression,
• decreased libido .

Visual effects

• internal hallucinations .

Minor effects

More common

• back pain,
• cough or hoarseness,
• constipation,
• fever or chills,
• headache,
• lower back or side pain,
• nausea,
• painful or difficult urination,
• runny nose,
• sneezing,
• stomach pain,
• stuffy nose,
• trouble sleeping,
• vomiting .

Less common

• diarrhoea,
• feeling faint, dizzy, or lightheaded,
• feeling of warmth or heat,
• flushing or redness of the skin, especially on the face and neck,
• lack or loss of strength,
• sweating .

Major effects

• blurred vision,
• confusion,
• difficult or troubled breathing,
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position,
• drowsiness,
• irregular, fast, slow, or shallow breathing,
• cyanosis,
• pinpoint pupils,
• relaxed and calm feeling,
• sleepiness,
• unusual tiredness or weakness .

Positive

• euphoria,
• sedation,
• pain relief,
• elevated mood,
• overall feeling of contentedness .

Neutral

• pupillary dilation .

Negative

• dysphoric mood,
• piloerection,
• nausea,
• vomiting,
• diarrhoea,
• muscle aches/cramps,
• yawning,
• lacrimation,
• mild fever,
• rhinorrhoea,
• insomnia,
• craving,
• sweating,
• distress/irritability .

Side-effects

• fever,
• irritability,
• muscle aches,
• sleeping difficulties,
• nausea,
• vomiting,
• constipation .

Risks

Short-term

• tolerance,
• accidents,
• constipation,
• overdose .

Long-term

• dependence,
• respiratory problems,
• if injected - damage to veins and circulation .

Dangerous interactions

Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption .

• Depressants (1,4-Butanediol, 2m2b, alcohol, barbiturates, benzodiazepines, GBL / GHB, methaqualone) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If unconsciousness occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If unconsciousness occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Stimulants - It is dangerous to combine buprenorphine, a depressant, with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of buprenorphine, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of buprenorphine will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only taking a certain amount of buprenorphine .

Dangerous

• Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
• MXE - This combination can potentiate the effects of the opioid
• DXM - CNS depression, difficult breathing, heart issues, hepatoxic, just very unsafe combination all around. Additionally if one takes dxm, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
• Cocaine - Stimulants increase respiration rate allowing a higher dose of opiates. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
• Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely.
• GBL / GHB - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position.
• Tramadol - Concomitant use of tramadol increases the seizure risk in patients taking other opioids. These agents are often individually epileptogenic and may have additive effects on seizure threshold during coadministration. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
• Benzodiazepines - CNS and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Blackouts/memory loss likely .

Caution

• PCP - PCP can reduce opioid tolerance, increasing the risk of overdose,
• Nitrous oxide - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.
• Amphetamines - Stimulants increase respiration rate allowing a higher dose of opiates. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
• MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhoea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases .

Withdrawal

Withdrawal from long-term use of buprenorphine may produce some symptoms similar to those experienced through heroin withdrawal. However, symptoms tend to be milder than for heroin or other opioids such as methadone withdrawal . Withdrawal symptoms vary from person to person, but may include -

• cold or flu-like symptoms,
• headache,
• sweating,
• aches and pains,
• difficulty sleeping,
• nausea,
• mood swings,
• loss of appetite .

These effects usually peak in the first 2 to 5 days. Some mild effects may last a number of weeks .

Harm reduction

Unlike methadone, the effect of buprenorphine on respiratory depression reaches a ceiling, therefore higher doses do not increase risk of respiratory depression to a significant degree.

However, if buprenorphine is used in combination with other central nervous system depressants, such as benzodiazepines and other CNS depressants, the combined effect on respiration can be life threatening .

Paraphernalia

If tablets are injected - needles and syringes, water, matches or lighter, spoon .

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