Suboxone, the partial agonist opioid buprenorphine combined with the opiate antagonist naltrexone, is used in the treatment of opioid dependence.  Since October, 2002, it can be prescribed by physicians who are addiction specialists or who have taken a special qualifying course from the American Academy of Addiction Psychiatry or several other organizations.  Buprenorphine, itself, is addictive and is abused by drug users, although carries less of a risk than a full-agonist opioid.

There are an estimated 800,000-1 million chronic opioid (heroin) users and over 6 million abusers of prescription narcotics.  (This appears to be a figure from 2000 and at least in central Pennsylvania the figures have skyrocketed since then, at least doubling.)  Abuse of prescription opioids is reported by 12% of 12-17-year-olds and 22% of 18-25-year-olds.  Between 1994 and 2001, there was a 352% increase in oxycodone ER visits and a 131% increase in hydrocodone visits.  Over 200,000 Americans are now receiving methadone maintenance in 947 different treatment programs.  Another 5,000 are taking the opioid antagonist naltrexone as a maintenance treatment.  Still more individuals are detoxed with methadone, naltrexone, clonidine or lofexidine, but not maintained on any medication treatment.  Emergency room admissions involving heroin have risen sharply from 36,000 in 1991 to 72,000 in 1995, and then to 90,287 in 2000, as have overdose deaths during the same period.

Naltrexone is not addictive and has a long half-life with treatment effects lasting up to three days.  It is not restricted like the highly addictive methadone and can be given by any physician.  However, compliance is poor and patients have to be first withdrawn for opioids before starting naltrexone.  Thus, it is ideal only for highly motivated individuals, such as health care professionals, business executives, and some individuals under pressure from the criminal justice system.  Unfortunately, the large majority (over 90%) of opioid-addicted persons relapse to opioid addiction after withdrawal, regardless of the withdrawal treatment method used.

France was the first country to extensively research and use buprenorphine with it being available in physician offices since 1996.  Currently, over 60,000 are being treated with it in France.

Buprenorphine is a partial opioid agonist. At low doses, it behaves as an agonist, and at high doses, it behaves as either an agonist or an antagonist depending on the circumstances. It is a partial agonist at the mu receptor and will displace morphine, methadone, and other full opioid agonists from the receptor. The partial agonist effects imbue buprenorphine with several clinically desirable pharmacological properties: lower abuse potential, safety if ingested inadvertently in overdose quantities, and weak opioid effects compared with methadone.

At low doses, buprenorphine is 20 to 50 times more potent than morphine. However, unlike morphine or other full agonists, the effects of buprenorphine are not linear with increasing dose, and it exhibits a "ceiling effect." The significance of the ceiling effect on respiratory depression is that an individual who takes too much of the drug is less likely to die from buprenorphine overdose, in comparison to overdose from other opioids. Some of the effects of buprenorphine are reversed at high doses, possibly because of its actions at the kappa opioid receptor. 

Buprenorphine can precipitate an abstinence syndrome if it is administered to a person maintained on a sufficient dose of a full agonist.  Because of the high affinity of buprenorphine for the opioid receptor, this precipitated abstinence syndrome cannot readily be reversed or overcome. Buprenorphine has tight binding to and slow dissociation from opioid receptors. It produces a blockade effect at the mu-opioid receptor so that subsequently administered opioids (such as heroin) do not produce their full euphoric or high effect.  Buprenorphine can produce euphoria (especially when injected), and it can produce physical dependence. However, it appears to produce less physical dependence than a full opioid agonist (such as methadone), and it may be easier to discontinue at the end of medication treatment.

Buprenorphine can be abused, especially intravenously, but it is less abuse prone than full opioids like heroin, methadone, Oxycontin, etcs.  To reduce the potential for abuse even further, a dosage form combining buprenorphine with naloxone has been developed (Suboxone).  If the combination form is dissolved and injected, the increased bioavailability of naltrexone will precipitate a withdrawal syndrome in individuals who are physically dependent on illicit opioids (such as heroin).

Daily dosage is from 1 mg to 32 mg. for up to one year.  It has few side-effects.  It is the mu receptor on which morphine, heroin, methadone, buprenorphine, oxycodone, and hydrocodone have their addictive effect.  Of these, all are full agonist, except buprenorphone, which is a partial agonist, giving only a 40% stimulation effect but blocking the receptor from further stimulation.  Naloxone and naltrexone are antagonist, attaching at and blocking the mu receptor without activating it.  The body develops tolerance to both agonists and partial agonists, meaning higher doses become necessary to achieve the same effect.  Physical dependence develops such that withdrawal symptoms with craving and discomfort occur from opioid agonists.  Healthy people do not die from opioid withdrawal.  Spontaneous withdrawal occurs when stopping or even decreasing opioid agonists.  Heroin withdrawal starts after 6-12 hours from the last dose, peaks at 36-60 hours, and lasts about 5 days.  Methadone has a longer half-life and the withdrawal is stretched out over a longer period, start 36-72 hours after the last dose.  The strength with which a medication binds to a receptor is referred to as its affinity for that receptor. The rate a medication uncouples from a receptor is referred to as dissociation.

Buprenorphine is a thebaine derivative opioid that is legally classified as a narcotic. It is available for use as an effective and safe analgesic in numerous countries. When used as an analgesic in the United States, buprenorphine is usually administered by injection, and doses are relatively low, compared with doses used to treat opioid dependence. The typical analgesic dose of buprenorphine is 0.3 to 0.6 mg (intramuscular or intravenous), and its analgesic effects last about 6 hours.

Buprenorphine has both a very high affinity for the mu receptor and a very slow rate of dissociation making it effective for a longer period of time.  Both agonist like heroin and antagonist have a hard time displacing it.  It can be given daily or three times a week or possibly even twice a week.

Buprenorphine has poor oral bioavailability, so it is administered sublingually in the form of tablets that are held under the tongue and absorbed through the buccal mucosa.  There are marked inter-patient differences in the sublingual bioavailability of buprenorphine, averaging 25-35%. Thus, the dose of buprenorphine should be adjusted to the clinical needs of the individual patient.  However, even a full 32 mg given to volunteers not accustomed to opioids has not caused significant difficulties.  It can cause withdrawal in patients maintained on 60 mg. of methadone a day, but can have agonistic effects in patients on 30 mg. per day. Buprenorphine-induced withdrawal is rarely severe. 

Generally, buprenorphine is started out with a low dose, under 8 mg., and after the patient is showing some sign of withdrawal.  Severely addicted patients require more time and caution.  Buprenorphine-induced withdrawal may come on more slowly than antagonist withdrawal.

In outcome studies, buprenorphine is as effective as methadone 60 mg/day, but not as effective as higher doses.  Buprenorphine has been successfully used for short-term withdrawal, but studies of other withdrawal modalities have shown that such brief withdrawal periods do not produce measurable long-term benefits in the treatment of opioid-dependent patients (Simpson and Sells 1990).  Long-term withdrawal is more effective, but long-period withdrawal remains a less effective treatment approach as compared with ongoing opioid maintenance treatment (Sees et al. 2000).

Because buprenorphine has poor bioavailability, swallowing the tablets will result in virtually no opioid agonist effects.  Buprenorphine causes no significant organ damage associated with chronic dosing; however, it may be associated with elevations in liver function tests.  The main side-effects are sweating and constipation.  Like methadone, buprenorphine produces physical dependence in the neonate and may produce a withdrawal syndrome in newborns.  In controlled studies in which buprenorphine was given to individuals taking known doses of opioids, the precipitated withdrawal syndrome was mild in intensity and easily tolerated.  The symptoms tend to be milder than those produced by naloxone-precipitated withdrawal (as well as other opioid antagonists), and intervention is rarely required.  Buprenorphine is metabolized by cytochrome P450 3A4, and it has the potential to affect and be affected by numerous other medications (inhibitors, inducers, or substrates) that use the same enzyme system.

Sublingual naloxone has relatively low bioavailability (Preston et al. 1990), while sublingual buprenorphine has good bioavailability. Tablets of Suboxone contain a ratio of 4:1 buprenorphine to naloxone (that is, tablets of 2/0.5 and 8/2 mg of buprenorphine/naloxone).  If an opioid-dependent person (dependent on full mu agonists such as heroin or methadone) dissolves and injects a buprenorphine/naloxone tablet, then naloxone has good bioavailability, which results in a predominant naloxone effect. Under such circumstances, the opioid-dependent person should experience a precipitated withdrawal syndrome. 

Urine testing for the presence of drugs of abuse (such as morphine indicating heroin use; benzoylecgonine indicating cocaine use; and other drugs of abuse such as cannabis and benzodiazepines) can also be useful in assessing the patient. Strong consideration should be given to conducting urine testing at every visit.

There are three grades of signs and symptoms of opioid withdrawal. Grade 1 includes yawning, sweating, lacrimination (tearing), and rhinorrhoea (runny nose). Grade 2 includes mydriasis (dilated pupils), piloerection (goose bumps), muscle twitching, and anorexia. Grade 3 includes insomnia, increased pulse, increased respiratory rate, elevated blood pressure, abdominal cramps, vomiting, diarrhea, and weakness.

ASAM placement criteria: Acute intoxication or withdrawal potential, Biomedical conditions and complications, Emotional, behavioral, and cognitive conditions and complications, Readiness to change, Continued use or continued problem potential, and Recovery environment.

A patient who is pregnant should be strongly considered for methadone rather than buprenorphine treatment.  Patients who abuse opioids (but are not dependent) may be appropriate for buprenorphine treatment; for example, if they have a high risk of progression to dependence or are injecting opioids.  Patients with a history of good response to buprenorphine who have had their medication discontinued (such as due to incarceration) and are now at high risk for relapse (such as having recently been released from prison) may also be good candidates, although caution is needed in starting buprenorphine.  Since alcohol is a sedative-hypnotic, patients should be cautioned to avoid alcohol while taking buprenorphine. Persons with active or current alcohol dependence are not good candidates for office-based buprenorphine treatment. 

During the initial treatment period, maintenance patients should be seen on a weekly basis to assess if the patients are complying with the dosing regimen and handling the medication responsibly (for example, not losing it and storing it safely). Once a stable dose is reached and a urine sample free of illicit opioids is obtained, the physician may determine that less frequent visits (biweekly or longer, up to 30 days) are needed. An office visit once a month is considered reasonable for patients on a stable dose who are making appropriate progress toward treatment objectives, but the frequency of office visits is at the discretion of the physician. 

An exception to Federal confidentiality regulations permits a program director to communicate with the minor's parent, guardian, or other person authorized under State law to act in the minor's behalf if he or she believes that the disclosure is necessary to cope with a threat to the life or physical well-being of the adolescent applicant or someone else.  

If the physician has been following the patient for some time, and she has been maintained on buprenorphine/naloxone and becomes pregnant: Switch the patient to buprenorphine monotherapy to minimize risk of naloxone exposure.  Studies have shown that buprenorphine is contained in breast milk, but due to its poor oral bioavailability, there is probably not a sufficient amount of buprenorphine ingested and bioavailable to have an effect on the newborn (Marquet et al. 1997). Thus, breast-feeding can be recommended to the buprenorphine-maintained mother (as it is also in methadone-maintained mothers).  The FDA labels naloxone to be Pregnancy Category B: no known teratogenic effects in animals, but controlled studies have not been conducted in humans.  Buprenorphine neonatal abstinence syndrome (NAS), if it is to occur (NAS occurs in approximately 62% of exposed infants and 48% require treatment), begins within 48 hours of birth and continues for up to one week, with peak symptoms at 3-4 days.  To prevent the precipitation of withdrawal, buprenorphine should not be restarted until at least 12 hours after the last dose of the opioid analgesic.   While sublingual buprenorphine is not expected to have an FDA-approved indication for the treatment of pain, sublingual tablets are used as an analgesic in other parts of the world (such as New Zealand).

Ideally, the patient's first 1 or 2 days of induction dosing should occur in the office. Prescriptions for future doses may be written thereafter. This keeps the amount of opioids located in the office to a minimum. Following the initial dose, the patient should be observed in the physician's office for up to 2 hours. 

For patients not currently dependent of opioids, but need buprenorphine maintenance (e.g. an addict being released from prison), on the first day, the patient should receive a single, sublingual 4/1 mg dose of buprenorphine/naloxone medication (this is given as two 2/0.5 mg Suboxone tablets) and be monitored in the office. Assess for evidence of excessive opioid agonist effects, and if seen, treat these symptomatically. If the patient has a strong opioid agonist effect (nausea, vomiting, etc.), then the daily maintenance dose may be only 4/1 mg or 2/0.5 mg of buprenorphine/naloxone, or this patient may not be suitable for buprenorphine maintenance treatment.  On the second day, the response to the first day's dose should guide subsequent dosing. The dose can be increased by
2/0.5 - 4/1 mg each day until targeted outcomes are achieved.

For physically dependent patients, if the patient does not have objective signs of opioid withdrawal at the time of arrival in the office (More information on signs of withdrawal is presented in Module 7: Overview to Patient Assessment.), then he or she should not receive a first dose of buprenorphine, as it may precipitate withdrawal. Assess the time of last use and either have the patient return another day or wait in the office until evidence of withdrawal is seen.

A minimum of 12 to 24 hours should have elapsed since the patient's last dose of a short-acting opioid, so that he or she should be exhibiting early signs of opioid withdrawal. Patients who are experiencing objective signs of opioid withdrawal and whose last use of a short-acting opioid was more than 12 to 24 hours prior to the initiation of induction can receive a first dose of 4/1 mg of buprenorphine/naloxone. If opioid withdrawal symptoms subside over the following 20 to 40 minutes and then return after 2 to 4 hours, a second dose of 4/1 mg can be administered. The total amount of buprenorphine/naloxone received should not exceed 8/2 mg during the first day.

Tests for all relevant illicit drugs should be administered at least monthly. Although such testing can be performed on a number of bodily fluids and tissues (such as urine, blood, saliva, sweat, and hair), urine screening is the most common testing method. Urinalysis is easily obtained, relatively inexpensive, and quite valid. A number of manufacturers are producing combination urine collection and test kits that make office-based urine testing reasonable.  Most common drugs of abuse (such as cocaine, methamphetamine, heroin, or marijuana) are readily detectable in urine. The low-potency benzodiazepines, such as diazepam and chlordiazepoxide, are also readily detectable. However, clonazepam, flunitrazepam, and alprazolam can go undetected in urine samples. 

Urine specimens should be collected under monitored conditions because opioid-dependent persons may attempt to give adulterated or substituted specimens. Urine should be collected in a room where samples cannot be diluted or otherwise adulterated and where patients are not permitted to bring briefcases, backpacks, purses, or containers of any sort. Direct observation of the collection should be done by a same-sex staff member.

Patients who are receiving higher doses of methadone should be tapered to 30 mg per day. Patients should not receive buprenorphine/naloxone until at least 24 hours after their last dose of methadone; and then only at a minimal dose of buprenorphine/naloxone (2/0.5 - 4/1 mg). Buprenorphine dosing should begin when the patient shows objective evidence of opioid withdrawal.  Use similar procedures to those described for short-acting opioids and expect the maximum total first-day dose to be 8/2 mg of buprenorphine/naloxone. Patients should not receive any further doses of methadone after their first dose of buprenorphine.

The induction goal should be to raise the dose of buprenorphine as rapidly as possible without producing adverse effects. Nausea within 1 to 2 hours after a dose suggests that the dose is too high (an excessive opioid agonist effect). Opioid withdrawal 3 to 6 hours after a dose suggests too little buprenorphine has been given.

For patients who do not experience any difficulties with the first day of dosing, the fixed-dose schedule can be followed to complete induction using the buprenorphine/naloxone combination. If no serious side effects or evidence of withdrawal symptoms emerge within 2 hours of the administration of the first day's dose, the patient is ready to move on to the next step in induction. Henceforth, doses should be advanced by 4/1 - 8/2 mg each day, with a target dose of 12/3 mg to 16/4 mg per day, to be achieved within the first week unless side effects occur. If continued dose increases are indicated after the second day, have the patient continue dose induction with a maximum daily dose of 32/8 mg. Most patients stabilize on a daily dose of 12/3 - 16/4 mg daily. If a patient is requesting dose increases above the target dose range, evaluation should occur at the office so supervision of dosing and assessment of response could occur.

The method employed in all the studies for determining the dose for less-than-daily dosing regimens was to double (for every-other-day dosing) or triple (for every 3-day dosing) the required daily dose for the patient. For example, increase the dose on the dosing day by the amount not received on intervening days: if on 8/2 mg daily, switch to 16/4, 16/4, 24/6 mg on Monday, Wednesday, and Friday, respectively.  Some patients were more likely to have urine samples positive for opioids on the less-than-daily dosing regimens.

Regulations permit a program or office to release patient-identifying information to law enforcement if a patient commits or threatens to commit a crime on the premises or against program or office staff members. The program or office can supply the name, address, and last known address but cannot report a patient’s other crimes. 

A program or practitioner can release information in a situation posing immediate threat to the health of the patient and requiring immediate medical attention. Information can be released to medical personnel who need to treat the condition. This exception cannot be used to release information to family or non-medical personnel.

A Federal, State, or local court may authorize a program or individual practitioner to make a disclosure of confidential patient information only after following certain procedures and making certain determinations. A subpoena, search warrant, or arrest warrant is not sufficient by itself to require or permit disclosure, even if it is signed by a judge.  An order signed by a judge is needed.

Suboxone's half-life is 37 hours with peak concentration in 30-60 minutes.  Since Suboxone is secreted in breast milk, nursing is contraindicated, but the patient can be switched to plain buprenorphine.  I personally recommend requiring the patient to give permission to contact other doctors and pharmacies in the area in order to assure that the patient isn't doctor-shopping, i.e., getting Suboxone from two or more physicians at the same time.  It does not increase the Q-T interval (Ann Pharmacother 2006 Mar;40(3):392-6). 

Alcohol Drinking Reduced: In a rat study, higher doses of buprenorphine reduced alcohol drinking, reported through activation of the nociceptin/orphanin FQ-NOP receptor system.  Similar results have been reported as observed in humans. Biol Psychiatry 2006 Mar 11.

Buprenorphine Abuse Common in Countries Without Suboxone: Buprenorphine (Subutex) is according to epidemiological data and clinical experience abused on a large scale in the Czech Republic and for some drug dependent persons it becomes a principal intravenously applied drug. Cas Lek Ches 2006;145(1):59-60.

Chronic Pain Opiate Addicted Patients: Suboxone May Have Helped: Many patients with chronic pain have less than optimal therapeutic outcomes after prolonged treatment with opiate analgesics. In an open trial of 95 adults with chronic noncancer pain referred by local pain clinics for detoxification from long-term opiate analgesic (LTOA) therapy, all patients had failed treatment as manifest by increasing pain levels, worsening functional capacity, and, in 8%, the emergence of opiate addiction. Length of prior LTOA therapy averaged 8.8 years. After a minimum of 12 hours of abstinence from all opiate analgesics, patients were given low doses of sublingual (SL) buprenorphine or buprenorphine/naloxone. Daily SL dose of buprenorphine ranged from 4 to 16 mg (mean, 8 mg) in divided doses. Mean duration of treatment is 8.8 months. 86% experienced moderate to substantial relief of pain accompanied by both improved mood and functioning. Patient and family satisfaction was robust. Only 6 patients discontinued therapy secondary to side effects and/or exacerbation of pain. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome. Malinoff HL, et al. Rush Pain Center, Chicago. Am J Ther. 2005 Sep-Oct;12(5):379-84. Ed: Open trials are notoriously unreliable due to bias.  However, I thought this one worth saving.

Clonidine Not as Good as Suboxone for Teens: In a 28-day DB study of 36 teens ages 13-18 with opioid dependence, 72% of Suboxone, but only 39% of clonidine patients stayed in treatment. In addition, 61% of Suboxone but only 5% of clonidine patients participated in a naltrexone phoas requiring 3 negative urines within one week. Marsch LA, et al. Univ Vermont. Arch Gen Psychiatry 2005;62:1157-64.

Cognitive Impairment Less with Buprenorphine than with Methadone: In a randomized study of 46 drug-dependent patients after either 8 weeks of buprenorphine or methadone treatment, buprenorphine produced less impairment on cognitive functions in some of the subtests of the psychomotor battery than methadone. This difference is specially relevant when it comes to driving ability and social functioning.

Cost: Through the Illinois Buying Club, 60 8 mg Suboxone tablets costs $262.50.  The Medical Letter reported the cost as $287 in its Feb. 17, 2003 newsletter. In my area in rural Pennsylvania, fourteen 8 mg tabs of Suboxone cost $70-$100. Different pharmacies vary considerably.

Detox: Suboxone Did Better than Clonidine in Detox: In a 13-day random assignment study of 113 in-patients and 231 out-patients, bup-nx treatment with supportive interventions included appropriate ancillary medications and standard counseling procedures guided by a self-help handbook did better than clonidine with the same supportive treatments: 77% in-patients assigned to the bup-nx condition achieved success (retention + clean urines) vs. 22% with clonidine, and 29% of out-patients assigned to the bup-nx vs. 5% with clonidine.  A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Ling W, et al. University of California, Los AngelesA. . Addiction. 2005 Aug;100(8):1090-100. Over 90% of 100 patients with past detoxification treatments rated buprenorphine treatment to be as good as or better than their past treatments. Reports of a euphoric effect were minimal (7%) and no patients reported any generalized worsening of their opiate withdrawal symptoms. J Addict Dis 2006;25(1):23-31.

Detox: High Dose Protocol: In an open study of symptom relief of 10 patients withdrawing from heroin with a high-dose rapid tapering buprenorphine detoxification protocol and a comparison between 208 patients treated with a clonidine/dextropropoxiphene detoxification protocol and 246 patients treated with the high-dose rapid tapering buprenorphine, 24 mg of sublingually administered buprenorphine beginning when the patient judges himself to be in a withdrawal state followed by another three days of daily administered and rapidly decreased doses resulted in a significant reduction of withdrawal symptoms. When the clonidine/dextropropoxiphene protocol was replaced with this buprenorphine protocol the number of patients continuing in treatment immediately after discharge from the detoxification ward increased from 41% to 58%. Effects of a high-dose fast tapering buprenorphine detoxification program on symptom relief and treatment retention. Palmstierna T. Karolinska Institute, Stockholm, Sweden. . J Psychoactive Drugs. 2004 Jun;36(2):273-7.

Doctor-Shopping Big Problem in France: Out of a total of 64,326 prescriptions of buprenorphine by 1,313 physicians to 3,259 patients, doctor-shopping represented an incredible 18.6% of the delivered quantity. Doctor-shopping involved a minority of patients and was highly concentrated: 87 patients (3%) with doctor-shopping doses superior to 16 mg/day were responsible for 45.4% of the total. Pharmacoepidemiol Drug Saf. 2004 Jul. Assessment of doctor-shopping for high dosage buprenorphine maintenance treatment in a French region: development of a new method for prescription database. Pradel V, et al. Marseille, France. Ed: Such patients might inflate the figures for the success of therapy, since they might be more motivated to produce clean urines in order to obtain the profits from selling buprenorphine and they would be also more likely to claim benefit from the treatment.  As best as I can tell, the buprenorphine in France is not combined with naloxone. Much of it is sold on the street and shot up intravenously, which is unlikely to occur in the U.S. due to the naloxone.  However, I have heard of a Suboxone ring in central Pennsylvania (Philipsburg), near to where I work.  While suboxone might not make a person quite as as high as oxycontin, etc., it might have a high street value since some drug users not yet addicted to opiates might mistakenly think that it is less addictive.

Depressed Addicts Did Best; Other Psychiatric Diagnosis Considerably Worse: In a retrospective study of 206 dually diagnosed and non-dually diagnosed opioid-dependent patients, all had severe long-lasting heroin addiction and 68.4% were affected by psychiatric comorbidity. Long-term buprenorphine mean dose was 7 mg. The patients were divided into 5 subgroups: group 1: major depression (MD) 30%; group 2: generalized anxiety (GAD) (11%); group 3: personality disorders (PD), antisocial-borderline (22%); group 4: schizophrenia (SC)(6%); group 5: substance use disorder without overt psychiatric comorbidity (SUD) (31%). Group 1 had the highest retention rate at 12 months (72%) vs. group 2 GAD (39%), group 3 PD (18%), group 4 SC (8%) and group 5 SUD, without comorbidity (45%) (p=0.006, p<0.001, p<0.001, p=0.002). Opioid abuse in follow-up was generally the opposite of retention. Higher BUP doses were associated with less risk of illicit opioid use (p<0.001).

Dosage: Mean Maintenance Dose 6.5 mg/Day: A French retrospective report of 180 patients in mainenance as average of 47 months (4 years).

France: Buprenorphine Experience: Daily Supervised Dosing Good Idea: In most European countries, methadone treatment is provided to only 20-30% of opiate abusers who need treatment. In 1995, France allowed all medical doctors to prescribe buprenorphine (BUP) without any special education or licensing. This led to 65,000 patients per year on BUP, about ten times more than with more restrictive methadone policies. Physician compensation mechanisms, pharmacy services, and medical insurance funding all minimized barriers. Almost half of the estimated 150,000 problem heroin users are on BUP. Daily supervised dosing by a pharmacist for the first six months resulted in significantly better treatment retention (80% vs 46%) and lower heroin use. Intravenous diversion of BUP may occur in up to 20% of BUP patients and has led to various infections and relatively rare overdoses in combination with sedatives. Opiate overdose deaths have declined by 79%. Newborn opiate withdrawal in mothers treated with buprenorphine compared to methadone was reported to be less frequent, less severe, and of shorter duration. French field experience with buprenorphine. Auriacombe M, et al. Universite Victor Segalen, Bordeaux, France. . Am J Addict. 2004;13 Suppl 1:S17-28. In France, a two-year cohort study of patients treated with buprenorphine and a survey conducted during the first year of buprenorphine replacement were funded by the manufacturer, Schering-Plough. The results showed that more than two-thirds of patients remained on treatment, and that, overall, the patients' general condition improved. Prescrire Int 2006 Apr;15(82):64-70.

Heroin Reinforcing Value Blocked by 8/2 Suboxone Dosage, But Not Lower: In a study with volunteer heroin addicts, heroin break point values and subjective responses were significantly lower under 8/2 and 32/8 mg buprenorphine/naloxone compared to 2/0.5 mg. In addition, 2/0.5, 8/2, and 32/8 mg buprenorphine/naloxone dose-dependently reduced the receptor population by 74, 83, and 91%, respectively. Both 8/2 and 32/8 mg buprenorphine/naloxone were well tolerated and effective in reducing the reinforcing and subjective effects of heroin, relative to the 2/0.5-mg dose; 80-90% of mu receptors need to be inactivated in order to obtain significant reductions in heroin-induced effects. Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Comer SD, et al. Columbia University. . Psychopharm (Berl) 2005 Oct;181(4):664-75.

Intensive Suboxone Treatment No Better Than Weekly: In a 24-week randomized, controlled clinical trial with 166 opiate addicts, once-weekly did just as well or better than thrice-weekly medication dispensing or enhanced medical management and thrice-weekly medication dispensing. The mean percentage of opioid-negative urines was once weekly 44%; thrice-weekly medication dispensing, 40%; and enhanced medical management and thrice-weekly medication dispensing, 40% P=0.82). All three treatments were associated with significant reductions from baseline in the frequency of illicit opioid use, but there were no significant differences among the treatments. The proportion of patients remaining in the study at 24 weeks did not differ significantly once-weekly medication dispensing 48%, thrice-weekly medication dispensing 43%, and enhanced medical management and thrice-weekly medication dispensing 39% (P=0.64).

Monoamine Oxidase Inhibitors Safe: The phenylpiperidine series opioids, meperidine (Demerol), tramadol (Ultram), methadone and dextromethorphan and propoxyphene (Darvon), appear to be weak serotonin re-uptake inhibitors and have all been involved in serotonin toxicity reactions with MAOIs, including some fatalities. Morphine, codeine, oxycodone and buprenorphine are known not to be SRIs, and do not precipitate serotonin toxicity with MAOIs. Br J Anesth 2005 Oct;95(4):434-41.

Morphine Withdrawal Symptoms Reduced in Rats:  Reduced jumping latency and duration, and reduced nitric oxide in brain. Zhou YH, et al. Beijing Medical University. Yao Xue Xue Bao. 2002 Mar;37(3):175-7.

Methadone No Better than Buprenorphine: In a 1-year randomized, open-label study of 139 heroin-dependent patients in a community setting receiving individualised treatment regimens of buprenorphine or methadone, the estimated mean number of heroin-free days did not differ significantly: methadone (225), vs. buprenorphine (222). Buprenorphine was associated with an average 0.03 greater QALYs over 52 weeks (not significant). The total cost was $ 17,736 with methadone vs. $11,916 with buprenorphine; costs excluding crime were $ 4513 vs. $5651. A randomised trial of the cost effectiveness of buprenorphine as an alternative to methadone maintenance treatment for heroin dependence in a primary care setting. Harris AH, et al. Monash University, Melbourne, Australia. . Pharmacoeconomics. 2005;23(1):77-91. Also: Depressive symptoms improved in all subjects, with no difference between methadone and buprenorphine groups, suggesting no differential benefit on depressive symptoms for buprenorphine compared to methadone. Eur Psychiatry. 2004 Dec;19(8):510-3.

Methadone Did Better with Heroin-Cocaine Addicts: In a 12-week DB study of 162 dual addicts of daily sublingual buprenorphine (12-16 mg) or methadone (65-85 mg p.o.) and contingency management or performance feedback with contingency management subjects receiving monetary vouchers for opioid- and cocaine-negative urine tests, methadone-treated subjects remained in treatment significantly longer and achieved significantly longer periods of sustained abstinence and a greater proportion drug-free tests. Addicts receiving contingency management achieved significantly longer periods of abstinence and a greater proportion drug-free tests during the period of escalating voucher value, compared with those who received performance feedback, but there were no significant differences between groups in these variables during the entire 24-week study. Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Schottenfeld RS, et al. Yale University. . Am J Psychiatry. 2005 Feb;162(2):340-9.

Methadone Maintenance May be Better: In a review of 52 studies(12,075 participants), methadone maintenance treatment (MMT) was compared with methadone detoxification treatment (MDT), no treatment, different dosages of MMT, buprenorphine maintenance treatment (BMT), heroin maintenance treatment (HMT), and l-alpha-acetylmethadol (LAAM) maintenance treatment (LMT). Retention in treatment: MMT is more effective than MDT, no treatment, BMT, LMT, and heroin plus methadone. MMT proved to be less effective than injected heroin alone. High doses of methadone are more effective than medium and low doses. Use of heroin: MMT is more effective than waiting list, less effective than LAAM, and not different from injected heroin. No significant results were available for mortality and criminal activity. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. Amato L, et al. Rome, Italy. . J Subst Abuse Treat. 2005 Jun;28(4):321-9. Ed: Unfornately, many of the studies were not high quality, so the conclusions, especially in regards to buprenorphine, should be viewed with caution. In a different review of studies, low-dose methadone (20 mg per day) was less effective than buprenorphine (2-8 mg per day). Higher doses of methadone (>50-65 mg per day) was slightly more effective than low dose buprenorphine (2-8 mg per day). Br J Gen Pract. 2005 Feb;55(511):139-46. In the U.S., Suboxone is usually given at 16 mg/day.

Methadone did as Well as Buprenorphine in Small, Long-Term Study But More Side-Effects: In a small 3-year random assignment study of 53 opioid addicts, those assigned to sublingual buprenorphine maintenance did as well as those on methadone. The retention rate was 50% for methadone and 45% for buprenorphine (p = 0.786). Quality of life (QOL) and somatic complaints improved equally in both groups. Concerning physical symptoms at 36 months, logistic regression revealed significantly less stomach cramps (p = 0.037) and fatigue and tiredness (p = 0.034) in buprenorphine compared to the methadone. Moreover, the buprenorphine-maintained group showed significantly less additional consumption of benzodiazepines (p = 0.015) compared with methadone. Sublingual buprenorphine and methadone maintenance treatment: a three-year follow-up of quality of life assessment. Giacomuzzi SM, et al. Innsbruck, Austria. .  Scientific World Journal. 2005 May 24;5:452-68.

Methadone vs. Buprenorphine: In a small

Methadone vs. Buprenorphine IV: Both Make You Just as High: IV buprenorphine abuse occurs in 20% of French buprenorphine patients where naloxone is not added to the buprenorphine. In a U.S. study of opioid addicts after detox, volunteers where injected buprenorphine reported getting just as high as those injecting methadone. J Pharm Exp Ther 2005 Dec;315(3):1320-30.

Methadone Caused More Cognitive Impairment Relevant to Driving: In a randomized clinical trial in 62 drug-dependent patients under either buprenorphine or methadone treatment with testing before and after 8 to 10 weeks of treatment, patients under buprenorphine treatment showed partially better results in some of the domains tested. The used tests are relevant when assessing driving ability. There was a significant correlation between dose of buprenorphine and some test results. We also found a correlation between age and reaction time and between duration of opioid dependence and results in some subtests. Buprenorphine produces partially less impairment on cognitive functions in some of the subtests of the psychomotor battery than methadone. Less impairment on one portion of a driving-relevant psychomotor battery in buprenorphine-maintained than in methadone-maintained patients: results of a randomized clinical trial. Soyka M, et al. University of Munich, Germany. . J Clin Psychopharm 2005 Oct;25(5):490-3.

Misuse of Buprenorphine: In France today, the treatment of opiate and notably heroin addiction with high-dose buprenorphine (HDB) is widespread. Although this treatment has been successful to some extent, problems persist. One is that some percentage (estimated at 17-47%) of patients "misuses" their HDB, either by intravenous injection or inhalation. Presse Med. 2005 Jun 4;34(10):711-8.

Network Therapy: Network therapy (NT) employs family members and/or friends to support compliance with an addiction treatment carried out in office practice. In a random assignment study of 66 patients to either NT or medication management were inducted onto short-term buprenorphine maintenance and then tapered to zero dose. NT resulted in significantly more urine toxicologies negative for opioids than MM (65% vs. 45%) and more NT than MM patients (50% vs. 23%) experienced a positive outcome relative to secondary heroin use by the end of treatment. Network therapy: decreased secondary opioid use during buprenorphine maintenance. Galanter M, et al. New York University. . J Subst Abuse Treat. 2004 Jun;26(4):313-8.

Out-Patient: Suboxone Maintenance Patients Vastly Better in Out-patient Follow-up vs. Detox: Using a retrospective chart review of 30 opioid-dependent patients induced on buprenorphine maintenance therapy in an inpatient detoxification unit vs. 30 age- and gender-matched patients who underwent detoxification (with a tramadol taper) and referral to intensive outpatient treatment (IOP), patients maintained on buprenorphine had a markedly increased initiation of IOP and remained in outpatient treatment longer than patients who were detoxified (8.5 wks vs. 0.4 wks, p < 0.001).

Predictors of Success: None Differentiate Methadone Success vs. Buprenorphine Success: This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. Researchers did not find any factors that would strongly guide selection of one medication over others.

Pain Treatment: Fentanyl Patients 150% Higher Dosage Increase vs. Bupronorphine: In a retrospective study comparing changes in dosages of transdermal (TD) fentanyl and TD buprenorphine in patients with cancer and non-cancer pain from 400 medical practices in Germany of 448 patients with noncancer pain and 446 patients with cancer pain, percentile increases in dosages over the whole treatment duration and adjusted per day were much higher in patients taking TD fentanyl (P < 0.05): mean percentile intraindividual increases per day were 0.42% vs. 0.17% for cancer patients taking TD fentanyl and TD buprenorphine and 0.25% vs. 0.09% in noncancer patients (P < 0.001). Changes in the prescribed daily doses of transdermal fentanyl and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study. Sitti R, et al. University of Erlangen, Germany. Clin Ther 2005 Jul;27(7):1022-31.

Pregnancy: Narcotic Abstinence Less Severe in Newborns with Buprenorphine than Methadone Mothers: In a DB PC study of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg for pregnant addicts just prior to delivery found that the total amount of opioid-agonist medication administered to treat narcotic abstinence syndrome (NAS) in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates (93.1 versus 23.6; p=.13). Length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates (p=.021). Peak NAS total scores did not significantly differ between groups (p=.25). Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Jones HE, et al. Johns Hopkins University. . Drug Alcohol Depend. 2005 Jul;79(1):1-10.

Suboxone: Brings New Patients into Treatment: In a 26-week cross-sectional and longitudinal analysis of patients entering a clinical trial of buprenorphine in a Primary Care Clinic (PCC) and those entering a local Opioid Treatment Program (OTP), PCC subjects compared with OTP subjects were more likely to be male (77% versus 55%, p<0.01), full-time employed (46% versus 15%, p<0.001), have no history of methadone treatment (46% versus 61%, p<0.05), have fewer years of opioid dependence (10 versus 15, p<0.001), and lower rates of injection drug use (IDU) (44% versus 60%, p=0.03). The new-to-treatment PCC subjects were younger (36 years versus 41 years, p=0.001), more likely to be white (77% versus 57%, p=0.04), had fewer years of opioid dependence (7 versus 14, p<0.001), were less likely to have a history of IDU (35% versus 54%, p=0.07), and had lower rates of hepatitis C (25% versus 61%, p=0.002) than subjects with prior methadone treatment. Abstinence and treatment retention were comparable in both groups. Office-based treatment of opioid dependence brings new types of patients entering into treatment. Treatment outcomes with buprenorphine in a PCC do not vary based on history of prior methadone treatment. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Sullivan LE, et al. Yale University. . Drug Alc Depend 2005 Jul;79(1):113-6. Ed: In my experience, many patients coming into Suboxone treatment are opposed to methadone.  It appears that many have avoided treatment, not only because of the limited access to methadone clinics, but also due to the feared effects of methadone.

Testosterone Not Decreased as in Methadone: High-dose methadone causes testosterone deficiency and sexual dysfunction in many opioid-dependent men. In a study of testosterone, free testosterone, estradiol, SHBG, LH, FSH, and prolactin in 17 men on buprenorphine, 37 on high-dose methadone and 51 healthy blood donors, buprenorphine had a significantly higher testosterone level [5.1 vs. 2.8 for methadone; P < 0.0001] and a significantly lower frequency of sexual dysfunction (P < 0.0001) and did not differ from that of healthy controls. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. Bliesener N, et al. University of Bonn, Germany. . J Clin Endocrinol Metab. 2005 Jan;90(1):203-6.

Torsades de Pointes: Buprenorphine OK for Methadone Torsade de Pointes Patient: Authors report a patient who developed torsade de pointes while receiving high-dose methadone and was successfully inducted onto buprenorphine under close medical supervision. No clinically important QTc prolongation was observed in the acute setting or during follow-up. Krantz MJ, et al. Denver. Pharmacotherapy. 2005 Apr;25(4):611-4.

Intravenous use of buprenorphine tablets associated with rhabdomyolysis and compressive sciatic neuropathy. Ann Emerg Med 2006 Apr;47(4):396-7.

Researchers confirmed previous findings of neuropsychological impairment in long-term MMT recipients. Both patients receiving MMT and former heroin users in prolonged abstinence exhibited a similar degree of cognitive impairment. Cognitive dysfunction in patients receiving methadone maintenance may not resolve following methadone detoxification. Drug Alc Depend 2006 Mar 16.

Studies have shown that buprenorphine increases adherence to antiretroviral therapy as well as reduce the risk of HIV infection among injection drug users. HIV Policy Law Review 2005 Dec;10(3):23-4.

Buprenorphine Did Better Than Morphine for Pain: In a DB study, a transdermal system with 35 microg/h buprenorphine was applied to the first group of patients while the second group received 60 mg/day of sustained-release morphine. In both groups oral tramadol was administered to a maximum of 200 mg daily, in case of need. The administration of transdermal buprenorphine versus morphine resulted in significant differences in the physical pain (P = 0.01), mental health (P = 0.03) and vitality (P = 0.001). Buprenorphine in long-term control of chronic pain in cancer patients. Pace MC, et al. Second University of Naples, Italy. Front Biosci 2007 Jan 1;12:1291-9.