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38th Annual Medical-Scientific Conference of the American Society of Addiction Medicine

Miami, Florida / April 26-30, 2007

In a 2001 consensus statement, leading North American organizations in addiction and pain medicine agreed that addiction is a “primary, chronic and neurobiologic disease” that arises from a combination of genetic, psychosocial and environmental factors. That recognition of addiction as a disease came less than a year after the US government passed the Drug Addiction Treatment Act of 2000, creating a nationwide office-based addiction treatment program.

Pharmacology

Conventional opiate treatment programs utilizing methadone or levacetylmethadol have demonstrated efficacy, but the drugs also pose some problematic issues, noted addiction medicine specialist Dr. Angel Gonzalez, San Juan, Puerto Rico. Drugs such as heroin and methadone are full mu receptor agonists. “Full-agonist binding activates the mu receptor and is highly reinforcing,” he indicated. “The full agonist is the most abused type of opioid.”

Partial mu agonists such as buprenorphine cause less receptor activation, have less reinforcing effects and have lower abuse potential compared to full agonists. Like full mu receptor agonists, partial agonists produce increasing receptor-specific activity at lower doses. However, at higher doses that result in complete binding of all mu receptors, the maximum opioid effect is not achieved with partial agonists, stressed Dr. Gonzalez.

A mu receptor antagonist such as naloxone occupies the receptor without activating it. Non-activating binding by an opiate receptor antagonist blocks the binding of the full agonists that have the greatest abuse potential.

Repeated use of opioids that activate mu receptors lead to physical tolerance and dependence, Dr. Gonzalez noted. Withdrawal leads to a variety of symptoms that increase in severity before reaching a peak after several days and then gradually subsiding over several additional days. With heroin, spontaneous opioid withdrawal syndrome usually occurs over four to seven days, whereas spontaneous methadone withdrawal might require as much as two weeks to run its course, Dr. Gonzalez told listeners. In contrast, precipitated opioid withdrawal syndrome has an onset in minutes and usually lasts no more than a couple of days. With the mu antagonist naloxone, withdrawal syndrome may resolve in a half hour or less. Dr. Gonzalez explained, “Buprenorphine precipitates withdrawal only when it displaces a full agonist on the mu receptor. Because it only partially activates the receptors, buprenorphine causes a net decrease in activation, which leads to withdrawal.”

The sublingual buprenorphine/naloxone combination has several characteristics that make it useful in office-based opioid treatment. As a partial agonist, buprenorphine has a reduced abuse potential, although the potential is not totally eliminated. Naloxone is active when used parenterally but not in an oral or sublingual formulation. Opiate-dependent patients who crush, dissolve and attempt to inject the sublingual combination will not derive the effects they seek.

“If the patient is opioid-dependent, the naloxone may cause withdrawal symptoms,” noted Dr. Gonzalez. “That decreases the market for diversion. Naloxone also will block, or at least partly block, the opioid agonist effect of buprenorphine, so the drug remains safe even if diverted.”

Reduced Overdose Risk

As Dr. Gonzalez continued, buprenorphine has proved to be safe for acute or chronic dosing. Principal side effects are nausea and constipation, which tend to be less severe and more self-limiting as compared to other mu agonists. No evidence of significant disruption of cognitive or psychomotor function has emerged in clinical experience with the compound. Rare cases of reversible hepatitis with liver-enzyme elevation have been reported (Hervé et al. Eur J Gastroenterol Hepatol 2004; 16:1033-7). Clinical experience has indicated minimal risk of overdose; although possible, clinical trials have revealed no evidence of respiratory depression. When combined with other central nervous system depressants, buprenorphine overdose might occur.

“In France, where buprenorphine tablets [without naloxone] have been available for years, there have been reports of death from respiratory depression in patients who dissolved the drug and used it in combination with benzodiazepines,” Dr. Gonzalez informed delegates. “There is no absolute contraindication about using buprenorphine with benzodiazepines, but patients should be warned of a potential interaction. I probably would not use [it] if a patient clearly has a history of benzodiazepine use disorder.”

In clinical trials, the partial agonist has proven more effective than placebo and equivalent to moderate doses of methadone, stated Dr. Laura McNicholas, addiction medicine specialist and Assistant Professor of Psychiatry, University of Pennsylvania, Philadelphia. In a large, randomized clinical trial, heroin addicts received buprenorphine doses ranging between 1 and 16 mg for 16 weeks (Ling et al. Addiction 1998;93:475-86). All but the 1-mg dose (included as a substitute for placebo) reduced heroin craving to a similar degree.

Buprenorphine maintenance and withdrawal strategies were compared in a randomized trial involving 40 patients (Kakko et al. Lancet 2003;361:662-8). Patients received maintenance therapy with sublingual buprenorphine 16 mg/day or withdrawal treatment with buprenorphine for six days followed by placebo. Patients randomized to withdrawal relapsed quickly after active treatment ended, whereas patients on maintenance therapy remained on treatment.

It was compared with and without naloxone in a small, randomized crossover trial involving patients on stable methadone maintenance regimens (Mendelson et al. Biol Psychiatry 1997;41:1095-101). Patients received intravenous doses of buprenorphine, naloxone, the combination, or placebo until they had completed four cycles of treatment. Buprenorphine alone had minimal opiate agonist effects. Naloxone alone caused rapid and severe opiate withdrawal symptoms. Intravenous injection of the combination resulted in withdrawal symptoms similar to those of naloxone alone.

“The buprenorphine/naloxone combination behaves like naloxone when taken intravenously,” stated Dr. McNicholas. “The abuse potential with buprenorphine/naloxone probably is very low in methadone-maintained patients.”

Abuse of Prescription Medicine

Though precise statistics are lacking, abuse of controlled prescription drugs poses a major public health challenge, according to a 2005 report from the Canadian Centre on Substance Abuse (Substance Abuse in Canada: Current Challenges and Choices). The report showed that Canada has some of the world’s highest per-capita consumption rates for prescription narcotics, sedative-hypnotics and prescription amphetamines. A Toronto-based study revealed that 11% of patients admitted for treatment of substance abuse in Ontario reported prescription drugs as a component of their abuse problem. A 2001 survey of US households showed that almost 10% of people aged 12 years and older had used prescription drugs for nonmedical purposes.

Clinical experience with sublingual buprenorphine/naloxone has demonstrated safety and efficacy in treatment of prescription drug abuse, according to Dr. Anton Bizzell, medical officer, Substance Abuse and Mental Health Services Administration, Rockville, Maryland. He presented data on 30-day treatment outcomes for more than 400 patients with abuse problems involving a variety of illicit and prescription opioid drugs. Retention rates ranged between 93% and 95% for patients who had abused heroin, non-heroin opioids, or a combination. Moreover, patient self-reported post-treatment outcomes were similar across the three patient categories. Overall, 84% of the patients abstained from all opioids other than buprenorphine during the treatment period, and 46% of the patients remained abstinent from all drugs and alcohol.

“A high proportion of patients treated with buprenorphine appear to be addicted to non-heroin opioids such as painkillers,” remarked Dr. Bizzell. “Buprenorphine treatment appears to be effective at 30 days in terms of retention in treatment, use of opioids other than buprenorphine, and abstinence from alcohol and other drugs.”

Real-world Experience

Dr. Richard Guzzetta, family medicine specialist, Touchstone Medical Group, Clovis, California, presented what he characterized as “real-world” clinical experience with buprenorphine/naloxone detoxification of patients with opiate addiction. He offered data on almost 300 patients enrolled in a two-week outpatient treatment program. While approximately 97% of the patients completed the two-week detoxification program, Dr. Guzzetta had no data on recidivism. However, he noted that the results appear promising with a marked turnabout from his experience with other strategies. “The results are just about the opposite of what I’ve seen with methadone,” he reported.

Noting his lack of affiliation with an academic or specialized substance abuse treatment program, Dr. Guzzetta remarked that his results show how community-based primary care physicians could offer effective treatment of opiate addiction.

Summary

Primary care treatment of opiate addiction can be accomplished with minimal risk of abuse or diversion with a sublingual formulation of buprenorphine/naloxone. As a partial opiate receptor agonist, it has a reduced abuse/diversion potential compared to methadone, which is a full agonist. The addition of naloxone in the sublingual formulation further reduces the potential for abuse or diversion by producing undesirable withdrawal symptoms if the compressed tablet is crushed, dissolved and injected.