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Buprenorphine was first synthesized in 1969 and human trials began in 1971. In animal models it demonstrated reduced dependence on opioids. The drug was approved for IV use in the US in the 1990s and for sublingual delivery for drug addiction treatment in 2002. Prior to 2002, it was a Schedule V drug (the lowest addiction level), but the FDA placed all buprenorphine products in Schedule III from that time onward, including injectable buprenorphine. It is a semi-synthetic drug, produced from thebaine just as are oxycodone, hydrocodone, hydromorphone, oxymorphone, etc.
It is a mixed agonist-antagonist drug found in Suboxone, Subutex, Zubsolv, Bunavail (for the treatment of addiction) and Butrans patches and Belbuca buccal films (for pain). It works by binding to the opioid receptors in the brain and spinal cord, partially activating them and blocking other opioids from reaching the receptors. It has a ceiling effect- meaning increasing the dose beyond 16mg a day results in no more effect than 16mg. In otherwords, 48mg a day has the same effect as 16mg a day, whereas 8mg has 96% of the effect of 16mg a day and 4 mg has 65% of the effect of 16mg a day. But these statistics are for single doses. Cumulative daily dosing shows that 4mg has nearly an identical effect as 16mg a day.
NEW THERAPIES: SUBLOCADE AND PROBUPHINE
Sublocade is a subcutaneous injection of buprenorphine that becomes a powder depot once injected, and slowly leaches into the circulation. It was first approved in November 2017 with a cost of $1,580 per month. If you have health insurance that will cover this injection (most do not), then it is an alternative to Suboxone, buprenorphine, Bunavail, or Zubsolv. It comes in 100mg and 300mg injections, with the cost being the same regardless of the injections.
Sublocade should be used as part of a complete treatment program that includes counseling and psychosocial support. Sublocade is a drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe. It is injected by a health care professional (HCP) under the skin (subcutaneously) as a solution, and the delivery system forms a solid deposit, or depot, containing buprenorphine. After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval. The safety and efficacy of Sublocade were evaluated in two clinical studies (one randomized controlled clinical trial and one open-label clinical trial) of 848 adults with a diagnosis of moderate-to-severe OUD who began treatment with buprenorphine/naloxone sublingual film (absorbed under the tongue). Once the dose was determined stable, patients were given Sublocade by injection. A response to MAT was measured by urine drug screening and self-reporting of illicit opioid use during the six-month treatment period. Results indicated that Sublocade-treated patients had more weeks without positive urine tests or self-reports of opioid use, and a higher proportion of patients had no evidence of illicit opioid use throughout the treatment period, compared to the placebo group.
The most common side effects from treatment with Sublocade include constipation, nausea, vomiting, headache, drowsiness, injection site pain, itching (pruritus) at the injection site and abnormal liver function tests. The safety and efficacy of Sublocade have not been established in children or adolescents less than 17 years of age. Clinical studies of Sublocade did not include participants over the age of 65. More information about sublocade is found here. Because the drug costs $1580 per month, regardless of whether the 100mg or 300mg dosage is used (300mg Sublocate equals about 30mg suboxone or buprenorphine per day at steady state after more than one injection), Algos will participate in the program, but because we cannot be guaranteed insurance company coverage, would have to have you arrange for payment for the medication, and are happy to write the script/ and obtain preapproval for the medication. It is likely most insurers will NOT cover this medication for several years given the cost per month being 3 times that of Suboxone and nearly 15 times the cost of buprenorphine tablets per month.
Probuphine
This is an implanted pellet containing buprenorphine that works for 6 months for those on very low dose (2-4mg/day) buprenorphine, and must sometimes be augmented with sublingual buprenorphine. The cost is over $10,000 per year, and most insurers are not covering this therapy.
Since buprenorphine it is a partial agonist instead of a full agonist like most other opioids, it does not result in a "buzz" or a "high" when taking it, and it lasts a very long time in the bloodstream with a half life of around 39 hours. This means after 24 hours, at least 3/4 of the dose from the day before is still in your bloodstream. Ultimately, daily dosing leads to an accumulation of the drug.
This means a 16mg dosage every 24 hours accumulates to give the same amount of buprenorphine in the bloodstream as a single 40mg dosage. Therefore many people are able to use only 4 to 8mg every 24 hours that gives the same amount as a 10-20mg given all at once. Using less of the drug cuts down on cost tremendously.
The DEA and other federal agencies prefer doctors use Suboxone, Zubsolv, or Bunavail (buprenorphine mixed with naloxone that causes instant withdrawal effects if injected IV and to some degree when snorted) to prevent abuse of the drug. Subutex (buprenorphine tablets without naloxone) is available for use during pregnancy.
QUESTION: Does the naloxone in the combination products Suboxone 8/2, Bunavail, Zubsolv, cause a lessening of the effectiveness of the buprenorphine if taken as prescribed sublingually?
ANSWER: For most people, no. The blood levels of naloxone reach only very low levels, 0.25ng/ml whereas the buprenorphine levels reach 2.8ng/ml. These levels are too low to reverse the effect of buprenorphine, and the naloxone lasts only one hour as shown below:
(Drug Dev Ind Pharm. 2015 Jan; 41(1): 79–84.)
To reverse the effect of buprenorphine it requires far higher doses of nalxone than this, and 8 times more IV than for other opioids in order to reverse the effect.
When trying to stop suboxone, subutex or equivalent it is important to move very gradually to very low doses (e.g. 1/8 of a 2mg/0.5mg strip) before trying to stop the drug. Otherwise due to the long action of the drug it may cause withdrawal symptoms.
Bunavail and Zubsolv are the latest drugs for addiction and because of better bioavailability, need less milligram amounts compared to Suboxone, but the dosages as supplied are accordingly lowered.
Suboxone, Zubsolv, and Bunavail are all listed as mg buprenorphine/mg naloxone. Naloxone is a complete blocker and will drive all opioids off the receptors potentially precipitating withdrawal but only if given IV. Suboxone or equivalent, buprenorphine, or naloxone all cause withdrawal effects by displacing the opioids that are already on the receptors.
OVERDOSE PREVENTION
Q: Is it possible to overdose and die taking buprenorphine? A: Yes, if taking high doses of buprenorphine and alcohol and/or benzodiazepines (such as Xanax, Klonopin, etc) within 6 hours of the buprenorphine dosage. The overdose rate is lower than other opioids, but in one mortality series, buprenorphine was listed as the main cause of death 14% of the time. Most of these patients had benzodiazepines and/or alcohol more than 50% of the time, and other opioids (e.g. heroin, morphine) the remainder of the time.
Q: How to prevent overdose deaths? A: 1. Don't mix drugs 2. If you are going to drink or use benzodiazepines, then take your entire daily dosage of buprenorphine in the morning and wait at least 6 hours before adding any benzodiazepines or alcohol. This is still not safe as it is mixing drugs, but safer than spreading out the dosing of buprenorphine or taking the day's supply of buprenorphine within 3 hours of alcohol/benzodiazepine use. Make it an absolute to not use benzodiazepines and alcohol within 6 hours of each other since these augment respiratory depression and death.
Klonopin (clonazepam) in some studies showed a higher safety profile than other benzodiazepines, so if you must take benzodiazepines, switching to low dose Klonopin is strongly suggested.
There are other medications that are available for the treatment of anxiety such as gabapentin, SNRI antidepressants (e.g. Effexor- venlaxifene), SSRI (Paxil, Prozac), Buspar, TCA (Elavil, Pamelor), and beta blockers (propranolol, metoprolol), etc. that have a much better safety profile compared to benzodiazepines, are not highly addictive as are benzodiazepines, and do not cause respiratory depression in combination with opioids or alcohol as do benzodiazepines.
Once on benzodiazepines, some people have to take them for the rest of their life because they do not know how to get off of them. Sudden withdrawal may precipitate full blown seizures, so very gradual withdrawal by small reductions in the dosage (not the frequency) over 2-3 months allows people to get off these dangerous drugs. Doctors are the greatest problem in getting people off of benzodiazepines since once they start prescribing, they nearly never try to wean patients off, and simply re-write the prescription month after month, year after year. After awhile, doctors don't even know why they are prescribing them, failing to ever test patient's anxiety with formal testing. Benzodiazepines used for sleep actually make sleep quality worse by interfering with REM sleep. Patients do go to sleep taking Restoril (tempazepam), Ativan (lorazepam), or other benzodiazepines, but stay in stage III and IV sleep, never entering REM sleep. They therefore wake up feeling exhausted and fatigued day after day.
Patients that are able to get off of long term use of benzodiazepines state it was as though a veil was lifted from over their head, they became interactive with family and friends, and did not suffer the chronic amnesia and fatigue that the benzodiazepines caused.