Summary/Abstract

Professionals at pain clinics could tailor treatment strategies by assessing a patient’s genetic risk for addiction, monitoring for misuse or abuse of prescription medication, evaluating emotional honesty and possibly prescribing a D2 agonist to “increase dopamine sensitivity,” according to a new study.

Content

MIAMI—For individuals presenting with pain, health professionals at pain clinics could tailor treatment strategies by assessing a patient’s genetic risk for addiction, monitoring for misuse or abuse of prescription medication, evaluating emotional honesty and possibly prescribing a D2 agonist to “increase dopamine sensitivity,” according to a new study.

“People are going to pain centers and their physicians are prescribing pain medications but maybe they don’t realize that some patients have genes that predispose them to addiction,” said Kenneth Blum, PhD, a lead researcher involved in the study. He presented the findings at the fall meeting of the American Society of Regional Anesthesia and Pain Medicine.

The study examined four components, each of which addresses different aspects of the nature of addiction. Researchers described the incorporation of these factors into a new treatment regimen as “a novel, neuro-therapeutic approach” that they have named the Reward Deficiency Syndrome Solution System.

Genetic Addiction Risk Score 

In a small pilot study, researchers used the genetic addiction risk score (GARS) to assess the extent to which genes can determine addictive behavior. Following a literature review, they identified six risk alleles and candidate genes that were associated with hypodopaminergic function and addiction: DRD2; SLC6A3 (DAT1); DRD4; 5HTTLLR; MAO-A and COMT.

Study participants were divided into two ethnically different groups of poly-drug abusers. The first study group consisted of 16 white men who used psychostimulant substances and the second group was composed of 10 heroin-addicted Chinese men. Risk severity was determined by calculating the prevalence of risk alleles in each group and using an arbitrary severity score based on the percentage of risk alleles and candidate genes.

All 26 of the study participants had at least one risk allele at 100% and 56% of the men in both groups carried the DRD2 A1 allele. Of all the participants, 74% had a moderate to high GARS. However, the groups did not significantly differ in terms of overall severity (67% vs. 81%) in these two distinct populations.

A larger GARS study also was conducted with 80 participants from two substance abuse treatment centers: the G&G Holistic Addiction Treatment Center, North Miami Beach, Fla., and Malibu Beach Recovery Center, Malibu Beach, Calif. In addition to the original six genes analyzed in the pilot study, another three were added: DRD3, OPRM1 and GABRA3, with 18 alleles for women and 17 alleles for men. Researchers calculated a risk severity code using an algorithm.

Researchers found that 86% of participants (n=70; due to poor DNA extraction, The Institute of Behavioral Genetics at the University of Colorado, Boulder could not provide DNA results for 10 of the original participants), had a moderate to high GARS, similar to the result of the pilot study.

The Addiction Severity Index (media version) was implemented to ascertain whether a correlation existed between the subjectivity of the questionnaire and the objectivity of the GARS test. “The final outcome for this evaluation awaits final testing of about 450 people,” Dr. Blum said.

“Based on our investigation utilizing nine genes [and alleles], we are consistently finding a moderate to high genetic risk in patients identified with drug addictive behaviors,” Dr. Blum said. “However, most interestingly, there are differences observed among these tested patients in terms of what specific gene polymorphisms (variants) are found. This will have great significance in terms of future therapeutic targeting of gene polymorphisms and even medication monitoring.”

Comprehensive Analysis of Reported Drugs 

Further to establishing patients’ risk for addiction is monitoring their existing use of prescribed and nonprescribed drugs for compliance and potential misuse or abuse. “The conundrum is that doctors do not know if the patients who are coming in to be treated for pain are also addicts,” Dr. Blum said. “They [doctors] can obtain psychosocial information, but how accurate is it? A lot of times, addicts lie.”

Using the comprehensive analysis of reported drugs (CARD), a questionnaire developed by Dominion Diagnostics, researchers evaluated 10,570 patients at substance abuse centers across six states over a two-year period from 2010 to 2011. During the study, 21,140 urine samples (two per participant) were analyzed for compliance with treatment medications and abstention from drugs of abuse. Additionally, 1,380 samples from 690 methadone-taking participants, and 2,744 samples from 1,372 participants taking the addiction treatment Suboxone (buprenorphine and naloxone, Reckitt Benckiser) were tested.

The researchers found that every reported prescription drug and drug of abuse were present in both the first and last urine sample. Compared with patients on methadone and Suboxone, fewer of the general treatment population complied with prescribed treatment medication (methadone users, 92%, Suboxone users, 88%; general population, 67%). Furthermore, fewer members of the general population (39%) abstained from drugs of abuse (including but not limited to opioids) compared with 51% for methadone users and 52% for Suboxone users. Dr. Blum said that although there is a higher compliance rate for patients on methadone and Suboxone, they still continue to abuse drugs, “In fact, we found that, for example, in the Suboxone group, the drugs of abuse found in the urine utilizing CARD were 47% opiates—surprisingly higher than we expected. So although both methadone and Suboxone have beneficial effects, we have not found the ‘magic bullet’ as yet.”

Interactive Voice Response System

Based on the premise that long-term opioid users can experience depression, the researchers sought to further quantify this assessment by gauging what they term the “true emotionality” of the patient, using an interactive voice response system. Patients’ responses were recorded on a web server and the affect in speech was analyzed for expressiveness, self-awareness and empathy using validated Gaussian mixture modeling. Results showed that patients on long-term opioids, including methadone and Suboxone, had a “significantly flat affect (P<0.01),” consistent with depression, compared with the general population and the Alcoholics Anonymous community.

KB220Z Neuroadaptogen Complex

Researchers evaluated the effects of KB220Z—a dopamine transporter (D2) agonist that was developed by Dr. Blum—on the brain’s reward circuitry, in a triple-blind, randomized, placebo-controlled, crossover study. One hour after administration of KB220Z, five heroin addicts with an average abstinence period of 16.9 months were given a functional magnetic resonance imaging test, and 10 psychostimulant drug abusers with an abstinence period of at least nine months underwent a quantitative electroencephalography.

Results showed that, compared with placebo, “KB220Z induced a blood oxygenation level-dependent activation of caudate-accumbens dopaminergic pathways, reduced the higher dopaminergic activity in the putamen and in 10 subjects, three brain regions of interest were found to be activated from resting state (P<0.05),” according to the study, which suggested a “putative, anti-craving/anti-relapse role for KB220Z by direct or indirect dopaminergic interaction.”

Andrea Trescot, MD, a pain management specialist with Orthopaedic Associates of St. Augustine in Florida, and a member of the Pain Medicine News editorial board, said, "I already use a company called 'Prove' to test for genetic susceptibility to addiction. The [study] material is very important. The poster actually described four different studies … genotyping pain patients at entry for opioid addiction risk, urine monitoring for compliance, evaluation of depression via computerized, voice-activated screening and pharmacologic support to increase dopamine sensitivity. This represents the first time, in my knowledge, that genetics have been incorporated into a global treatment algorithm” 

Asked to comment on the study, Andrew Kolodny, MD, president of Physicians for Responsible Opioid Prescribing and chair, Department of Psychiatry, Maimonides Medical Center in New York City, said, “It’s clear that [the researchers] are looking to identify a genetic factor related to opioid addiction. The reason to look for a genetic link is if you thought of opioid addiction as a genetic illness, but if you understand it as resulting mainly from exposure to opioids, then my impression of the study is that it doesn’t make much sense to me," Dr. Kolodny said. "With alcohol it’s different: It does make sense to genetically study those who are addicted because most people who drink are not alcoholics. But when it comes to highly addictive drugs, searching for an addiction gene makes less sense because many people with repeated or prolonged exposure to the molecule will get addicted. With highly addictive drugs, it may actually make more sense to study the genes of those who can use without getting addicted. Something you see in the pain community is that they make the mistake of thinking about opioids in the same way they think about alcohol,” said Dr. Kolodny.

In response to Dr. Kolodny’s remarks, Dr. Blum said, “In due respect, while it is correct that high doses of opioids may result in physical addiction, it is not true that opioids and alcohol are different neurobiologically in terms of net dopamine release. To state that ingestion of opioids is not an illness is true, but Dr. Kolodny is missing the real issue concerning addiction per se. According to the American Society of Addiction Medicine, addiction is indeed a “brain disorder of impairment of the reward circuitry.” It does make sense to evoke stratification of “genetic risk” for incoming pain patients because this can result in a gateway to further addictive behaviors including other drugs.”

Dr. Kolodny added, “Some drugs are inherently more addictive than other drugs and that’s my point—that when it comes to highly addictive drugs, it may make more sense to look at the genes of people who can use highly addicted drugs without getting addicted and see what’s different about their genes.  So I’m not saying there’s no genetic role: I’m saying that we need to think about alcohol and opioids differently, and opioids are highly addictive drugs, so to look for an addictive gene doesn’t make much sense to me.” 

Dr. Blum is chairman of the board and chief scientific officer of LifeGen Inc, the company that holds exclusive licenses for his patents for KB220Z. Dr. Blum is the inventor of GARS and is working on commercialization with Dominion Diagnostics LLC and LifeGen Inc. Dr. Blum is a member of the Scientific Advisory Board at Dominion Diagnostics. Dr. Kolodny reported no conflicts of interest. Dr. Trescot is medical director of Pinnacle Labs.  She is also on the speakers bureau of Eli Lilly, Pfizer and Janssen.