The United States is experiencing an epidemic of heroin addiction and a sharp rise in opiate over-dose death. Contrary to addicts being introduced to opiate addiction through street heroin, 75% of new addicts became addicted through prescription opiates. When the OxyContin becomes too expensive ($80/pill), people switch to the cheaper street heroin ($5-10/hit). Nora Volkow of NIDA, Tom Frieden of the CDC, and Michael Botticelli of the President’s Office of Drug Control Policy have advocated the expansion of methadone programs and buprenorphine treatment to respond to the epidemic. SAMSHA, the federal agency which regulates methadone maintenance programs, suggests that we call these interventions “Medication Assisted Treatment” (MAT) rather than opiate substitution programs so as not to stigmatize people.
SAMSHA’s New Rules
Methadone programs have been around since the mid-1950s in New York State. Under the Narcotic Treatment Act of 1974, methadone maintenance clinics became legal in the United States, although states vary in state regulations. What is new is that SAMSHA has effectively rewritten the rules on how methadone maintenance clinics are run. Whereas the law of 1974 limited methadone to those who had been addicted for a year, the SAMSHA (2012, Tip 43) guidelines allow for those who are not physically dependent on opiates to receive methadone. While initially the goal was to wean patients off, SAMSHA (2012) advises directors of clinics when a patient requests a dosage reduction that they should “educate” the patients on the importance of staying on their Medication Assisted Treatment. There is no duration limit on MAT. Moreover, there is no longer a limit on dosage. Given that stress is a reliable precipitant to relapse in drug abusers, SAMSHA discusses increasing dosage during stressful times (see page 77, in SAMSHA’s Tip 43, Medication-Assisted Treatment).
Buprenoprhine is a Partial Agonist?
The newcomer on the scene for treatment of opiate addiction is buprenorphine. The drug company characterizes buprenorphine as a “partial agonist” at a mu-receptor and an antagonist at a kappa receptor. In the body, there are 3 types of receptors for opiates: mu receptors, kappa receptors, and delta receptors. Mu receptors produce the pleasurable effects and the compulsion to use opiates. Kappa receptors counter the mu-effects. Upon hearing that buprenorphine is a partial agonist, I wondered “how?” I’m always amazed at the amount of information available to biologists. For almost all receptors, someone knows the shape of the receptor, the amino acids in the receptor that a ligand (neurotransmitter or drug) interacts with, the proteins in the body of the neuron that are influenced when the ligand binds, and the downstream effects on the ligand/receptor binding. So what is making buprenorphine different from methadone, morphine, and OxyContin? It did not take long to find out.
Turns out that buprenorphine not only interacts with the mu-receptor but also another protein called a “Regulator of G-protein Signaling” which turns off activity at the mu-receptor. The problem is that tissues and brain areas vary in terms of whether the neuron contains the “Regulator of G-protein Signaling.” As such, buprenorphine will only demonstrate an effect on some outcome measures but not on others. Thus it will be a “partial agonist” on some measures but not on others. The case has been made that buprenorphine is less likely to produce an overdose via respiratory depression than other opiates. However, all bets are off if buprenorphine is used with another drug. Many people on buprenorphine die when they combine “bup” with alcohol.
Opiate Agonists Are Very Dangerous Drugs
Methadone and buprenorphine compete for the same enzymes as many antibiotics, antidepressants, and antipsychotics for their metabolism (removal from the body). As such the effective dose of methadone is much higher than when people are not on these other medications. In addition, methadone can result in cardiac arrhythmias because of a change in electrical conduction in the heart (QTc prolongation), although buprenorphine is supposed to be a safe on this outcome. However, many antidepressants and antipsychotics can also increase QTc prolongation. With regard to danger associated with cardiac arrhythmias, the probability of an adverse event increments with each additional drug. Studies of opiate overdoses find that antidepressants, benzodiazepines, and antipsychotic drugs are associated with lethal overdoses. The SAMSHA guidelines recommend screening for co-occurring disorders. The Tip 43 guidelines do mention those medications which compete for the same enzymes as methadone but don’t discuss risks associated with multiple medications that increase risk of cardiac arrhythmias.
Dilemma of Other Addictive Drugs in Methadone Maintenance
It has been known for a long time that many heroin addicts do not limit their drug consumption to heroin. When people are in methadone maintenance, they often don’t quit using cocaine, marijuana, or alcohol. (In terms of drug interactions, there is some suggestion in the literature that concurrent use of marijuana actually decreases the opiate dosage required to curtail cravings.) While SAMSHA does suggest that Opiate Treatment Programs screen for other drugs, SAMSHA is unclear about what should happen if the urine tests positive. (According to SAMSHA instructions, we are to use the language ‘tests positive’ rather than ‘dirty urines.’) SAMSHA is clear that patients should not be dis-enrolled from the program. Sanctions can include limiting take-home dosages of methadone. They also suggest switching the patient to naloxone.
When I read the suggestion to switch to Naloxone, I was really confused. SAMSHA seems to want to avoid an addict’s use of street heroin at all costs. Naloxone will displace all opiates (buprenorphine, heroin, morphine, methadone) from the mu-receptor but won’t induce any signaling in the neuron. In fact, naloxone will displace natural opiates (endorphins) from the receptor as well such that even any placebo effect on pain suppression is lost. In terms of listed side effects, naloxone causes anxiety, a decrease in pain tolerance, joint and muscle pain, and induces immediate withdrawal signs if taken by someone who is dependent on opiates. There’s a history of poor compliance among addicts with naloxone. SAMSHA knows this. Why would they introduce a drug option that could undermine all their efforts to set up a self-sustaining high compliance program?
To be fair here, naloxone does decrease relapses in alcoholics who are trying to maintain sobriety. So we can call it “evidence-based treatment.” Drug addicts are not going to crave their drug(s) of choice when taking naloxone. The problem is that with naloxone patients aren’t going to want anything else either, such as food, going to work, etc. (Yes, naloxone has been considered as a potential treatment for obesity.) Of course the drug companies don’t include measures such as lethargy and apathy when they publish the drug trials, but the impact is clear in the animal literature.
So we’re back to the real problem of what to do about methadone and “bup” patients that use other drugs. Especially when used in combination with alcohol, methadone and buprenorphine can induce overdose. Another complicating factor with the SAMSHA’s goal of increasing the numbers on MAT is the paucity of knowledgeable clinicians who approve of MAT in America. About 45% of the non-physician clinicians in substance abuse treatment in this country are persons in recovery. They generally are strong adherents to Twelve Step Principles. The goal for Twelve Steppers is freedom from all mood and mind altering drugs. They don’t generally approve of MAT. Historically, physicians in Addiction Medicine often are recovering people as well. So where are all these substance abuse professionals to staff methadone maintenance clinics going to come from? The danger in by-passing the current work force and developing a new work-force is that it will take some time for the new recruits to develop expertise in detecting when a client is abusing alcohol and knowing the population.
Methadone for Pain Versus Methadone for Addiction
Ironically, while the government’s response to the opiate epidemic is to increase MAT with more liberal dosing practices, they are also more closely monitoring pain clinic doctors. At a recent International Opioid Conference I attended in Boston, most of the presenters were doctors working in hospice or pain clinics. The lawyers talked about pain-management doctors being entrapped by clients working for the DEA and then facing criminal charges and fines. (The director of prestigious Stanford pain-management clinic was recently visited by the DEA.) At the conference, the director of the Stanford clinic talked about his clinic’s response to the DEA scrutiny. They have developed very rigorous screening batteries to detect those pain clinic patients most likely to become addicts; they have developed elaborate informed consent procedures entailing a 20 minute video presentation for all prospective patients; they implemented drug screening procedures with point of care methods followed by laboratory screening involving very expensive assays. The bottom line is that costs have increased dramatically, further contributing to the cost of medical care, which presently is already the most expensive system in the world. This all seemed ironic to me, because if given a pain patient is indeed an addict, then the protocol is to refer to methadone or buprenorphine treatment for addiction. Once the patient becomes a methadone or buprenorphine patient, doctors are to “educate” the patient about the dangers of ever trying to become abstinent. Moreover, the rationale for methadone is that the dosage is to be sufficiently high so that tolerance develops such that heroin, at any dose, will fail to produce an effect (opiate blockade).
Given that buprenorphine is now in a clinical trial to treat medication resistant depression, we’re probably going to have a lot of people taking opiates. Then we’ll have many dilemmas over what to do if the patient escalates the “bup” dose without permission or uses an unapproved medication. Physician may wonder whether they need parole officer training. But, whatever the outcome for the patient, more money will be spent on drugs, monitoring, and auxiliary personnel. Thus, the U.S. is embarking on another big experiment with the drug companies and another big increase in the cost of medical care in this country.
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Leece, P., Cavacuiti, C., Macdonald, e. M., Gomes, T., Kahan, M., Srivastava, A., Steele, L., Luo, H., Mamdani, M. M., & Juurlink, D. N. (2015). Predictors of opioid-related death during methadone therapy. Journal of Substance Abuse Treatment, in press.
McCance-Katz, E. F., Sullivan, L., Nallani, S. (2010). Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. American Journal of the Addictions, 19(1), 4-16.
Zedler, B., Xie, L., Wang, L., Joyce, A., Vick, C., Brigham, J., Kariburyo, F., Baser, O., Murrelle, L. (2015). Development of a risk index for serious prescription opioid-induced respiratory depression or overdose in Veterans’ Health Administration patients. Pain Medicine, in press.
Zedler, B., Xie, L., Wang, L. Joyce, A., Vick, C., Kariburyo, F., Rajan, P., Baser, O., & Murrelle, L. (2014). Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Medicine, 15, 1911-1929.
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