A.T.F. Volume VII, #2. Spring 199

Alcohol and MMT
MMT Patients and The Perils of Pain
From the Editor
Events to Note
The Naltrexone Nexus ­ Part 1
Where to Get Info
Readers Survey Response ­ Coke Confounds MMT

Events to Note

For additional postings & information, see: www.atforum.com

July 1998

Medical Review Officer Training Course

July 16-18, 1998

San Diego, CA

Sponsor: Amer. Society of Addic. Med.

Contact: 301-656-3920 www.asam.org

August 1998

UCSD Summer Clinical Institute in Addiction Studies

August 3-6, 1998, LaJolla, CA

Sponsor: U of CA School of Medicine - San Diego

Contact: www.attc.ucsd.edu/

E-mail: mki@ucsd.edu

September 1998

Comorbidity Across the Addictions

September 25-27, 1998

Newcastle upon Tyne, United Kingdom

Sponsor: Elsevier Science

Contact: 44.1865.843.643

E-mail: a.richardson@elsevier.co.uk

American Methadone Treatment Assn. Annual Conference

September 26-29, 1998

New York City

Sponsor: AMTA

Contact: Talley Management

609-423-7222 ext. 350, NEW Web site: www.assnmethworks.org

October 1998

National Harm Reduction Conference

October 7-10, 1998

Cleveland, OH

Sponsor: Harm Reduction Coalition

Contact: 501-843-8048

12th Annual National Meeting on Alcohol, Other Drug & Violence Prevention in Higher Education

October 15-18, 1998

Washington, DC

Sponsor: US Department of Education

Contact: 800-676-1730 www.edc.org/hec/natl/1998

Review Course in Addiction Medicine

October 22-24

Chicago, IL

Sponsor: ASAM

Contact: 301-656-3920 www.asam.org

[To post your event announcement in A.T. Forum and/or our Web site, fax the information to: 847/413-0526 or submit it via e-mail from http://www.atforum.com]

The Naltrexone Nexus ­ Part 1

Setting the Stage

The tale of naltrexone, and its cousins ­ naloxone and nalmefene ­ is a drama filled with some misconceptions, controversy and, many would say, exploitation. Still, as the plot unfolds, it appears that naltrexone heroically emerges as a most useful and potent member of the addiction professional's therapeutic repertoire.

Naltrexone is a non-addicting, mu opioid receptor antagonist linking together, like a nexus, three different addiction treatment objectives ­ opiate detoxification; relapse prevention following detox; and alcoholism recovery treatment. It has also been variously investigated as an aid to treating eating disorders, autism, Alzheimer's disease, and other maladies.

Opioid antagonists were first reported in 1915, when N-allylnorcodeine was observed to block the respiratory depressant effects of morphine and heroin. In the 1940s, nalorphine was synthesized, but its dysphoric effects discouraged widespread use for treating morphine intoxication. Naloxone, an allyl derivative of noroxymorphone was synthesized in 1960. [1]

Naloxone was more potent and less toxic than nalorphine, and produced no dysphoria, but its short duration of action following oral administration made it unsuitable for long-term use in blocking the euphoric effects of opioids. The development of naltrexone in 1963 was motivated by the need for a longer- acting, orally potent opioid antagonist. [1]

The biochemistry of these agents was facilitated by the fact that relatively minor changes in the structure of an opioid could convert a drug that is primarily an agonist into one with antagonistic actions at one or more types of opioid receptors. Thus, morphine was transformed into nalorphine, and oxymorphone into either naloxone or naltrexone. [2]

It is believed that naloxone and naltrexone are relatively pure antagonists that may interact with all classes of opioid receptors, although with different affinities. A more recent development, nalmefene, is a mu receptor antagonist that is reportedly longer-acting and more potent than naloxone when taken orally. [2] Nalmefene is undergoing clinical investigation by various researchers.

Relapse Prevention Therapy

Naltrexone was conceived as a long-term drug dependency recovery therapy for eliminating drug cravings and opioid-seeking behavior, and thus helping to prevent relapse. During the early 1970s, the National Institute on Drug Abuse funded clinical studies to establish naltrexone for this purpose and obtain FDA approval.

A.T. Forum spoke with Richard B. Resnick, MD ­ Clinical Associate Professor, New York University School of Medicine and Executive Director, Center for Psychiatry & Family Therapy, New York City ­ who was among the first researchers to perform Phase II clinical trials in 1973 to assess dosage efficacy of naltrexone. It was tested as a therapeutic medication following opiate detoxification, but Resnick quickly found that to be most successful naltrexone needed to be part of an overall psychosocial treatment program.

According to Resnick, naltrexone is a specific remedy to aid in extinguishing "conditioned abstinence" ­ i.e., the well-ingrained cues that trigger opiate cravings and relapse. "People go back into their communities following detox and they have all these 'bells go off,' similar to classically conditioned reflexes, and they automatically get cravings leading to relapse."

"While they're on naltrexone, patients know that heroin won't have any effects for satisfying those cravings. We've found that half the patients challenge naltrexone by taking heroin just to see if it works the way we said it would ­ no effect ­ and the other half believe us and don't waste their money buying heroin," he says.

Some researchers believe that the patient's taking heroin (or another opiate of choice) while on naltrexone, and then experiencing no opiate effects to satisfy or reinforce the triggering cues, is actually necessary for extinguishing the learned drug behaviors and associated cues. In other words, they claim, the therapy works best if patients emit the behavior (opiate taking) that is to be extinguished while naltrexone is in their systems to block any desired and/or expected effects. [3]

This concept is still somewhat controversial. Resnick doesn't subscribe to the necessity of the patient's challenging naltrexone with opioids for it to work, but that it is necessary for patients to be repeatedly exposed to environmental cues (conditioned stimuli), without reinforcement by opiates, in order for conditioned craving and conditioned abstinence to be extinguished.

Prescription For Action

Naltrexone has a sufficient half-life (approximately 14 hours; with a 24-hour duration of action) to permit once-a-day dosing, and its prescription does not require special administration. However, it is contraindicated for use in persons actively using opiates, since it produces immediate withdrawal symptoms (abstinence syndrome) with potentially serious effects. [1,4] A period of at least five days abstinence from opiates is necessary ­ ten days abstinence from methadone.

The drug undergoes extensive first-pass metabolism in the liver, [1] and practitioners have been cautioned regarding the potential for liver damage at higher doses, especially in patients with already compromised liver function. [5] However, at least one recent investigation observed no adverse clinical or laboratory changes in liver function associated with high-dose naltrexone therapy. [6]

Resnick's typical prescription calls for 100 mg of naltrexone on each Monday and Wednesday and 150 mg on Friday ­ an average of 50 mg/day over the week. He finds this dosage blocks all effects of heroin for up to 24 hours at a time, without any impact on liver function.

He believes that to extinguish the various conditioned cues, this regimen should be followed for nine to twelve months. Beyond that, the patient is advised to carry a tablet at all times [sort of like a condom] to use in advance "like an insurance policy" if there is a risk of relapse, such as at a gathering of old friends who are still abusing opiates.

Of course, ongoing motivation and compliance with naltrexone maintenance treatment can be problematic, and there have been high attrition rates in some research trials. [1] All the patient has to do is skip the drug for a day or two and then opiates will have their original effects. At those times there is a serious risk of overdose, since the patient has lost any previously developed tolerance to opiates ­ plus, the long term administration of antagonists increases the density of opioid receptors in the brain, which might cause an exaggerated response to opioid agonists. [2]

Resnick says it is often best to have the patient monitored by another responsible person ­ a parent, significant other, or even an employer in some cases. It has been noted that professionals, such as lawyers or healthcare workers, who are threatened with the loss of licenses for relapsing, tend to have additional motivation to comply. [1] Resnick suggests that certain professionals ­ doctors, pharmacists, nurses ­ may need to continue daily naltrexone therapy indefinitely as long as they have ready access to opiates at work.

He stresses that, "naltrexone by and of itself does nothing other than protect the patient from possible effects of opiates, and it has no effects on stimulants like cocaine. Rather than the medicine being the treatment, it is the medicine that allows treatment to take place." Counseling, family therapy, participation in 12-step groups, psychiatric evaluation, and other psychosocial or medical interventions are vitally important. He notes that about half of his naltrexone patients are also prescribed antidepressants as part of the overall treatment regimen.

Awakening Interest?

Resnick expresses disappointment that naltrexone-mediated opiate relapse prevention therapy has not been more widely embraced by the addiction treatment community, and few heroin addicts are informed about its availability. Those who are given prescriptions are merely instructed to take it daily ­ advice that few follow on their paths to relapse. Some treatment providers either focus solely on abstinence, shunning any adjunctive medications, or on methadone maintenance without considering alternative modalities, he observes.

Until fairly recently, pharmaceutical companies have also neglected naltrexone, in Resnick's opinion, "initially by failing to support clinical trials and subsequently by failing to actively market its use in opiate dependency treatment. Consequently, many substance abuse treatment providers have not been informed about naltrexone's unique role in facilitating relapse-prevention."

However, with FDA approval of naltrexone for alcoholism treatment in 1994, there has been an awakening of commercial interest. As Resnick observes, there are 20 million alcoholic abusers who might now benefit from naltrexone, compared to roughly 600,000 opiate addicts.

Some enterprising treatment providers have also rallied to the potential of opioid antagonist-mediated detoxification (via naloxone) followed by naltrexone therapy for relapse prevention. This approach has engendered some controversy, in part due to inadequate research.

Future installments of this article on "the naltrexone nexus' will explore the alcoholism treatment and antagonist-mediated detoxification issues.

References:

1. Gonzales JP, Brogden RN. Naltrexone: A Review of its pharmacologic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs.1988;35(3):192-213.

2. Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. [CD-ROM]. New York, NY: McGraw-Hill; 1993.

3. John David Sinclair, PhD, personal communication. For a related discussion, see: Researcher: Naltrexone minus drinking equals failure. Alcoholism & Drug Abuse Weekly. May 12, 1997;9(19):1,6.

4. Judd LL, panel chair. Effective Medical Treatment of Heroin Addiction. Consensus Development Statement. Bethesda, MD; National Institutes of Health, November 19, 1997. Available at: http://odp.od.nih.gov/consensus/statements/cdc/108/108_stmt.htm. Accessed March 5, 1998.

5. Physicians' Desk Reference. Montvale, NJ: Medical Economics Co.; 1998.

6. Marrazzi, MA, et al. High-dose naltrexone safe for liver. Amer J Addns. 1997;6:21-29.

Where to Get Info

Two From Haworth Worth A Look

Addiction Interventions Examined

The Integration of Pharmacological and Nonpharmacological Treatments in Drug/Alcohol Addictions (ISBN 0-7890-0375-9), discusses how traditional "clean and sober" recovery methods are being combined with "drug solutions" to successfully treat addictions. Edited by Norman Miller, MD, this well-researched book is filled with practical clinical findings geared toward reducing morbidity and mortality due to long-term drug abuse and dependence.

One section of interest lists over 60 drugs used for detoxification, maintenance, relapse prevention or withdrawal from opiates, cocaine and/or alcohol. Some of the medications are currently unavailable in the U.S., while others might not be typically thought of for those applications.

Miller notes, "We need a step-by-step progression from research findings to the development of clinical standards to produce more effective medications."

Second JMA Explores MMT

This second edition of the Journal of Maintenance in the Addictions continues the exploration of critical issues facing the methadone treatment field. Major articles focus on: quality assurance using outcome indicators, an evaluation of the safety and labeling of LAAM, how counselor attitudes affect MMT, the role of methadone advocacy, and an examination of MMT's genesis in New Zealand. Plus, there are important messages from key associations and practitioners in the field, most notably: an update from Mark Parrino (AMTA) on managed care, changes in regulations/oversight, and the coming accreditation process; and Joyce Woods' (NAMA) observations on penal attitudes and methadone treatment.

This is the only journal of its kind for healthcare professionals, administrators, advocates, and others interested in where MMT has been and where it's headed. As such, it deserves support from the field, both in terms of subscriptions and contributions of articles.

To purchase the book or subscribe to JMA, contact Haworth Press at: 1-800-429-6784; outside U.S., call 1-607-722-5857. E-mail: getinfo @haworth.com.

Readers Survey Response ­ Coke Confounds MMT

Cocaine Use Prevalent

In the fall 1997 edition of A.T. Forum [Vol. VI, #4] ­ and at our Web site: www.atforum.com ­ readers were asked to share their clinical experiences regarding patients in MMT programs who are also abusing or dependent on cocaine. Our article on the subject reported research indicating that from 16% to 75% of patients use cocaine to some extent while in methadone treatment.

Readers were asked, "What percentage of patients first entering your MMT clinic are also cocaine users?" The average reported by those responding to the survey was 43%. [Range: 2 - 90; Median: 40; Mode: 50; SD: 24.5.]

It is interesting to observe that this finding also approximates the average of the earlier reported results: i.e., (16 + 75)/2 = 45.5%. However, it should be noted, the question in our survey focused on cocaine use upon first entering MMT, whereas other findings looked at usage during treatment.

Thus, while in treatment, some patients expectedly discontinue their cocaine use and others may continue or, perhaps, begin use anew. This is consistent with our article, which noted that some addicts may use cocaine as a stimulant to self-medicate potential sedating effects of methadone, possibly due to methadone over-medication, and others may simply indulge in cocaine because they no longer need to support an expensive heroin habit and have more money for that purpose. A reader's letter suggested some additional reasons:

• "Patients can't get high on heroin anymore." [due to methadone blockade]
• "Patients miss the ritual of getting high, or are still chasing the ultimate high.'"
• "Talking about cocaine triggers usage in some patients."
• "It also seems that once a client enters MMT and is stabilized after a few months, boredom sets in," the reader wrote. Some patients apparently miss the "old drug routine" and experiment with cocaine.

Clinic Reactions

Our article also suggested that few MMT programs have treatment protocols specifically for patients who abuse both cocaine and opioids. Readers were asked: "Does your MMT clinic have a specific program for cocaine users?" Their responses:

Yes = 25%;

No = 70%;

Don't Know = 5%

Thus it appears that most clinics are not prepared to effectively deal with cocaine problems among their patients. This may be due to a lack of funding or reimbursement for such specialized programs or added resources; however, our survey did not assess the particular reasons.

As we also reported, clinics have varying routine behavioral interventions for counteracting cocaine abuse. Readers were asked: "How does your MMT clinic typically deal with patients who continue to use cocaine?" Here were their responses, in rank order:

76% - Decrease or stop take-home privileges.

73% - Increase counseling.

55% - More frequent urine testing.

47% - Increase group therapy.

40% - Methadone detox and dismissal.

28% - Increase methadone dose.

26% - Other.

14% - Decrease methadone dose.

Readers were asked to check all that apply, so responses total greater than 100%. As can be seen, the counterproductive practice of decreasing methadone dose was at the bottom of the list, and increased counseling was near the top. However, a significant percent indicated the punitive practice of methadone detoxification and dismissal from the program, although it is not known to what extent cocaine use or rule infractions might have progressed before such severe actions were deemed necessary.

Reader Comments

Under the "other" category, a number of those responding indicated acupuncture treatments or referral to the medical director and/or psychiatric evaluation. Several other approaches included:

• · cocaine detox and 90-day probation
• · referral to an inpatient cocaine treatment program
• · behavior contracts for non-use of cocaine
• · encourage participation in 12-step groups (e.g., Cocaine Anonymous).

A California physician said he prescribes amantadine [a dopamine agonist sometimes used for cocaine relapse prevention] 100 mg four times daily. And, one highly selective clinic in Georgia solves the cocaine dilemma by not letting patients into the program at all if anything but opioids shows up in their urine screens.

A letter from a large clinic in Pennsylvania indicated that the program director has instituted special "Quitting Cocaine, the First 30 Days" sessions for entering MMT patients to educate them on the medical complications of the problem. Continuing cocaine users, who constitute 15-25% of about 500 patients, are given a warning period of 30 days and a revised treatment plan. In the event of opiate or cocaine relapse, patients are given increases in methadone dose and attend mandatory relapse therapy groups.

Thus, with an average of over four out of ten patients using cocaine upon entering MMT, as indicated by our survey, this represents a highly significant treatment challenge. In a few instances, readers reported that as many as 90% of patients were using both cocaine and opiates upon entering treatment. Certainly, this is an issue warranting further research and constructive action by MMT program clinics.