Pauline Anderson
Medscape Medical News 2008. © 2008 Medscape
March 15, 2008 — Brain scans of patients in a methadone treatment program who were exposed to various visual cues confirm that these formerly heroin-dependent subjects still respond to drug-related visual stimuli.
The imaging study, appearing in the March issue of the American Journal of Psychiatry, shows that patients' cue-induced craving is heightened just prior to once-daily methadone dosing compared with just afterward.
Their findings could explain why so many patients who are on methadone keep using heroin, said the study's lead author, Daniel D. Langleben, MD, an assistant professor of psychiatry from the University of Pennsylvania, in Philadelphia.
"This is essentially providing objective, observable evidence that, indeed, the time of increased vulnerability to relapse in patients in a regular methadone maintenance program is in the time before [receiving] the dose," he told Medscape Psychiatry. Their observation, he added, suggests some addicted people might need more frequent or higher dosing of methadone or a related drug to reduce their risk for heroin relapse. "This provides the template for how to test for that," he said.
Objective, Observable Evidence
The 25 patients in the study had been receiving daily methadone through a methadone maintenance program for a mean of 54 months. They were studied on 2 separate occasions, 3 to 4 weeks apart, once 90 minutes before and once 90 minutes after receiving their scheduled daily methadone dose, and so at the low point and at the peak of methadone plasma levels (the sessions were randomized and counterbalanced). Fifteen participants took part in both sessions, and 6 in the predose session alone and 4 in the postdose session alone.
The study sessions involved scanning the brain using functional magnetic resonance imaging (fMRI) while the subjects were shown a series of 24 heroin-related pictures and 24 non–drug-related pictures, all displayed very quickly. The process of selecting these images took several months, with each drug-related image painstakingly matched to a nondrug image.
"We went as far as humanly possible" to create the "ideal match," said Dr. Langleben. A picture of a pair of hands injecting heroin in the forearm, for example, was matched to an image of a similar pair of hands holding a kitchen implement. If a human body part — a knee or an elbow, for example — appeared in the drug image, again, there would be the same body part in the control image. Even the lighting and backgrounds of the images were carefully constructed.
Both pre- and postdose sessions resulted in limbic neural activation but, compared with the postdose session, the predose session induced significantly greater activation in the amygdala, hippocampus, and insula — regions associated with craving and relapse. This observation suggests that methadone-maintenance patients remain vulnerable to drug cues and that this vulnerability may be highest just before the expected dose.
"From our interpretation, these patients are vulnerable because the limbic system is still responding to drug cues in the same way it would be expected to respond if these patients were untreated heroin addicts on the street," said Dr. Langleben.
Findings May Explain Relapse
Dr. Langleben believes that this finding provides a clue as to why a significant percentage of patients in methadone treatment programs relapse. "Here is the possible answer as to why people on methadone maintenance continue to occasionally use — but still use — heroin," he said. "Occasional use still has all the risks of intravenous heroin use, which are the infections, the hepatitis, and the need to procure the heroin, which leads to people selling their methadone."
This study demonstrates how fMRI can be used as a clinical tool to determine whether a patient on a maintenance drug regimen needs a higher dose or a different treatment. It is important to establish, for each individual, the "normative range" of brain response to a standard set of stimuli, which will reveal individual vulnerabilities, said Dr. Langleben.
"You have a person in methadone maintenance and you send them for a test like this and see what the response is," he told Medscape Psychiatry. "It might tell you that this person is vulnerable, so maybe you say this person needs twice-a-day dosing, or maybe this person needs a longer-acting preparation such as buprenorphine," another opiate-agonist therapy. Or, he added, the testing could determine that at some point treatment is unnecessary.
Is This Anything New?
In an accompanying editorial, Bryon Adinoff, MD, from the department of psychiatry at the University of Texas Southwestern Medical Center, in Dallas, questioned whether the results of the study — that once-daily dosing may not suffice for some patients — tells researchers anything new. "Several decades of accumulated evidence may suggest that the once-daily dosing for methadone maintenance may not be sufficient for a large number of patients," he writes.
However, he praised the neuroimaging used in the study. "Although perhaps only confirming clinical observations described over decades of study, there is something particularly convincing about seeing our clinical insights confirmed in the visual images of neurobiological activation," he concludes.
The study was supported by grants from the National Institute on Drug Abuse and by the VA Mental Illness Research, Education, and Clinical Centers. All authors report no competing interests.
Am J Psychiatry. 2008;165:390-394 Abstract, 303-305. Abstract
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