Cunning, Baffling, Powerful

© Nico Smit | 123rf.com

Vincent Dole was one of the three physicians who originated methadone as a maintenance drug treatment for heroin addiction in the 1960s. Rather unexpectedly, he was asked to serve as a Class A, non-alcoholic, trustee for the General Service Board of Alcoholics Anonymous. He thought they had made a mistake so before accepting the position, he discussed his research into “chemotherapy for narcotic addiction” with executives of the A.A. Fellowship. They didn’t see any problem or conflict of interest with his appointment and Dr. Dole served as a trustee for A.A. for eleven years, from April of 1965 until April of 1975.

At one point in his tenure as a trustee, he served as a co-chair for the General Service Board. In his farewell letter to the A.A. GSO, printed in the August-September issue of Box 4-5-9, the newsletter from the General Service Office of A.A., he said he would always remain identified with A.A. “My heart is with the Fellowship.”

Like most in A.A., I have gained more in the association than I have been able to give. Especially, it has been a privilege to witness the power of love when focused and unsentimental. I have seen that: Salvation is found in helping others; help stems from knowledge, humility, compassion, and toughness; success is possible.My greatest concern for the future of A.A. is that the principle of personal service might be eroded by money and professionalism. Fortunately, most of the membership of A.A., especially the oldtimers, know that A.A. cannot be commercialized. It is not a trade union of professional counselors or an agency hustling for a budget. The mysterious wisdom of A.A. will discover how to cooperate in reaching out to sick alcoholics while maintaining its Traditions.

In a 1991 article he wrote for the journal Alcoholism, “Addiction as a Public Health Problem,” Dr. Dole said that throughout his time as a trustee he was puzzled by why he specifically was asked to serve. He ended by assuming he had been “brought in as a smoke alarm, a canary in the mine” to guard against “the Fellowship being distorted by aggressive person with dogmatic opinions.” Then, in the late 1960s, he believed a more specific reason emerged, not long before Bill W.’s death. An excerpt from that article is available here: “The Methadone/AA Link.”

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research I should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Dr. Dole went on to say he unsuccessfully sought to find that analogue in his laboratory until it closed in 1991. But he thought the work had just begun. Other laboratories and investigators would continue to work on the analogue problem. “With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.”

Since Dr. Dole made that optimistic prediction, several different medications have been used as a harm reduction strategy for individuals with alcohol dependence or alcohol use disorders. Two opioid antagonists, nalmefene and naltrexone and three drugs acting on the gamma-aminobutyric acid (GABA)ergic system (baclofen, acamprosate and toprimate) has been used formally or informally to reduce alcohol consumption or maintain abstinence. Recently in the journal Addiction, Palpacuer et al. did a meta-analysis of 32 double-blind randomized controlled trials of these five medications. The studies were published between 1994 and 2015, and had a combination of 6,036 patients between them. They concluded:

There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.

There was no evidence of any significant reduction in serious adverse events or mortality. Studies that sought to assess the efficacy of these medications as maintenance drugs, similar to how methadone is used, “were inadequate to investigate” whether they reduced serious adverse events. “In addition, any pharmacological approach that might benefit patients by reducing their alcohol consumption might also harm them because of safety issues.” As a result, the researchers advocated for long-term mega-trials exploring health outcomes.

To conclude, our results suggest that no treatment currently has high-grade evidence for pharmacologically controlled drinking in the treatment of patients suffering from alcohol dependence or alcohol use disorders. At best, some showed low to medium efficacy in reducing drinking, but across a range of studies with a high risk of bias. Although based on all available data in the public domain, this meta-analysis found no evidence of any benefit of the use of drugs aiming for a controlled drinking strategy on health outcomes. We invite researchers and stakeholders to set up a coherent agenda to demonstrate that pharmacologically controlled drinking can be translated into genuine harm reduction for patients. From the clinical perspective, while this new approach is often presented as a ‘paradigm shift’ in terms of therapeutics, doctors and patients should be informed that the critical examination of the pros and cons of the evidence clearly questions the current guidelines that promote drugs in this indication.

Reporting for The Guardian, Sarah Boseley further noted that one of the reasons for the inconclusive findings in Palpacuer et al. was because of the high drop out rates in the studies. “So many people dropped out of the trials that 26 of the 32 studies – 81% of them – had unclear or incomplete outcome data.” The lead author for the study, Clément Palpacuer, said the report did not mean the drugs weren’t effective. “It means we don’t yet know if they are effective. To know that, we need more studies.” There have also been concerns raised about the drugs by some studies already.

Bosley cited Fitzgerald et al., a review of the trial evidence used to approve nalmefene for use in the NHS. The researchers said at best, there was only modest evidence of efficacy in reducing alcohol consumption. This was despite stacking the deck in how the data was analyzed for approval of the drug.

Important weaknesses in nalmefene trial registration, design, analysis and reporting hamper efforts to understand if and how it can contribute to treating alcohol problems in general practice or elsewhere. The efficacy of nalmefene appears uncertain; a judgement of possible limited efficacy in an unusually defined and highly specific posthoc subgroup should not provide the basis for licensing or recommending a drug.

There are issues noted with baclofen as well. A co-author of Fitzgerald et al. noted one French study raised concerns with the safety of baclofen, with more deaths in the treatment group (7 of 162) than the placebo group (3 of 158). A further study by France’s medicines safety agency drew attention to additional adverse effects: “In particular, the risk of intoxication, epilepsy and unexplained death [on the death certificate] increases with the dosage of baclofen.” See “Sure Cure for Drunkenness” and “A ‘Cure’ for Alcoholism” and “The End of Alcoholism?” Part 1, Part 2 and Part 3 for more concerns with baclofen and nalmefene.

Vincent Dole’s search for a methadone analogue or adjunctive chemotherapy for alcoholism is unlikely to be successful. As Carleton Erickson pointed out in The Science of Addiction, alcohol is different than other drugs. He said: “Unlike other drugs, alcohol has no specific receptor to activate in the brain.” Cocaine works on the dopamine transporter. Heroin and other opioids work on the opioid receptor; and marijuana works on the cannabinoid receptor. “Alcohol is known to affect the GABA receptor, the NMDA receptor, and probably others.”

There isn’t a hand-in-glove fit between a receptor and alcohol as there is with the opioid receptor and heroin or other opioids. So there isn’t a medication that can single handedly block alcohol as there is with heroin and other opioids. As Bill W. knew from personal experience, alcohol is cunning, baffling and powerful.


I Smell a RAT

© antonihalim | Stockfresh.com

© antonihalim | Stockfresh.com

Medication Assisted Treatment (MAT) for addiction comes in various forms that are often (unhelpfully) lumped together into one category. Replacement or substitution methods, like methadone or Suboxone maintenance are radically different from using naltrexone to treat alcohol or opioid use disorders. Yet they are combined into the single category of MAT. While naltrexone is not a cure for addiction, it has been shown to help minimize cravings for urges for both alcohol and opioids. And there is some evidence emerging that it could be useful to blunt cravings for methamphetamine.

In 2010 Karlia et al. did a literature review on pharmacological approaches to treat methamphetamine use disorders. They concluded there was no substantial evidence for effective treatment at the time. “Clinical trials using aripiprazole [Abilify], GABA agents (gabapentin [Neurontin], baclofen, vigabatrin), SSRIs, ondansetron and mirtazapine [Remeron] have failed to show efficacy.” They noted where there was some indication where “agonist replacement medications” like d-amphetamine and modafinil may hold some promise.

The unavoidable problem with “treating” methamphetamine addiction with d-amphetamine is you are using a similarly addictive substance to “treat” methamphetamine addiction. Again, it repeats the error of opioid substitution/replacement therapy. While methamphetamine and amphetamine are Schedule II controlled substances, Modafinil still has an addictive potential as a Schedule IV. It is used to treat narcolepsy and shift work disorder, and it is touted as a “life hack” on Wall Street or “smart pill”—until you decide to stop taking it.

They also pointed to the work of Swedish researcher, Nitya Jayaram-Lindström, who showed in a 2005 study where naltrexone significantly reduced the subjective effects of dexamphetamine and blocked cravings in dependent patients. Additionally, the frequency and amount of amphetamine use was significantly reduced. A double blind study by Jayaram-Lindström in 2008 again showed the efficacy of naltrexone in reducing cravings and self-reported use of amphetamine. A further double-blind, placebo-controlled study by Jayaram-Lindström again demonstrated a significant reduction in cravings and self-reported use of amphetamine. “Naltrexone therefore appears to be a highly promising medication for amphetamine dependence.”

Now there is a study by UCLA researchers on naltrexone as a treatment for methamphetamine addiction. Here is a link to a pre-publication manuscript of the study by Ray et al. Again it was found that naltrexone blunted cravings for methamphetamine and lowered self-reports of subjective effects. Lara Ray, a UCLA psychology professor said: “The results were about as good as you could hope for.” The UCLA press release on the study and an article on The Fix by Zachary Siegel noted where clinical trials into the efficacy of naltrexone to treat methamphetamine addiction have already begun.

One clinical trial with naltrexone was completed and last updated in May of 2013 but no results are posted yet; and another study is ongoing. Although results for the complete trail by California Pacific Medical Center Research Institute were not posted on Clinicaltrails.gov, it does seem to be reported in a 2015 study by Pal et al. reported in the Journal of Addictive Medicine. There was not an improved treatment response found in this study. The Pal et al. study was quite small and does not really argue against further clinical trials into the potential use of naltrexone to treat methamphetamine addiction. The replication of Jayaram-Lindström’s results by Ray et al. are sufficient to see further research into this potential treatment.

The side effects from naltrexone are minimal, making it a viable medication to assist addicts trying to establish and maintain abstinence from dependence upon alcohol, opioids, and now—apparently—methamphetamine. Substitution or replacement medications for addiction need to be distinguished from other medications such as naltrexone within the catchall category of MAT. Perhaps they would be better labeled as SAT—Substitute Addiction Treatment—or RAT—Replacement Addiction Treatment—instead of MAT, Medication Assisted Treatment. Personally, I’m partial to RAT.


Look Before You Speak

© Panpalini | Dreamstime.com - Toad Photo

© Panpalini | Dreamstime.com – Toad Photo

I am concerned about an article I read recently on alcohol treatment, “The Best Treatment for Alcohol Use Disorder Your Addiction Counselor Isn’t Telling You.” It seemed like it was more of a rant than an attempt to constructively make a point. The author is an epidemiologist who wanted people to know that “medication is a vital key” in treating addiction. But some of the comments he made were surprisingly biased for someone who is “a published healthcare statistician and epidemiologist currently pursuing a doctorate in epidemiology.”

One example of this is a study from the Journal of Alcohol Studies that he linked in his article. He cherry picked how the study found that 29% of a sample of A.A. members said they received some pressure to go off their medication (of any type). But he failed to report that over half of the A.A. sample believed that using relapse-preventing medications “either was a good idea or might be a good idea.” Seventeen percent didn’t think that it was a good idea to take relapse-preventing medications; and only 12% said they would tell another member to stop taking it. Sixty-nine percent of these didn’t listen and continued taking their medication. The conclusions from the article’s abstract were:

The study did not find strong, widespread negative attitudes toward medication for preventing relapse among AA members. Nevertheless, some discouragement of medication use does occur in AA. Though most AA members apparently resist pressure to stop a medication, when medication is prescribed a need exists to integrate it within the philosophy of 12-step treatment programs.

He described the benefits of two medications for treating alcohol use disorder, Naltrexone and Campral (acamprosate) and claimed that: “ These medications are very likely the ones that your counselor or sponsor is not telling you about. In fact, the majority of the rehabs in the United States do not use any of this medication.”  The author made, but did not support that claim.

The rehab I work for part time knows of and supports the use of both of these medications and has done so for a number of years. A.A. sponsors might be violating their Traditions in recommending or telling people they sponsor that they should try Naltrexone or Campral. They certainly would be involved in ethically questionable advice-giving since their sponsor role is not as a doctor or an addictions professional.

The most disturbing claim was that “Naltrexone is an opioid inhibitor that has been FDA approved as a constant low dose (daily intake) or as a supplement prior to drinking.” He noted its use to inhibit cravings for chronic alcoholics, cautioning that it could “up-regulate” the opioid system and cause worse relapses when the person was off Naltrexone. Then he suggested that it was best served as an “emergency relapse drug.” From the article:

Patients, prior to relapse, have taken this drug and report significantly lower impact of their relapse. In fact, naltrexone works so well to reduce relapse that many alcoholics use it to successfully drink on a regular basis with very few reports of high binge drinking. It is entirely possible that rather than going to AA meetings, the majority of alcoholics in the near future can simply carry a bottle of naltrexone with them for drinking occasions.

I’ve reviewed information on Naltrexone from Medline Plus, WebMD, Drugs.com, and SAMHSA (Substance Abuse and Mental Health Services Administration) here and here. I did not find ANY indication that Naltrexone was “FDA approved” as a supplement prior to drinking. To be sure, Naltrexone is an FDA-approved medication for alcohol dependence. But there was no indication that Naltrexone was approved as a “supplement prior to drinking” or as an “emergency relapse drug” that “many alcoholics use it to successfully drink on a regular basis with very few reports of high binge drinking.”

There have been studies that indicated Naltrexone led to reduced drinking in both the amounts of alcohol and the frequency of drinking. And there have been studies where individuals used Naltrexone to limit or control their drinking, as with pharmacological extinction in the Sinclair Method. Here is an article written by John Sinclair, after whom the method was named. There is also information on the Sinclair Method here and on Facebook. Also see my article, “A ‘Cure’ for Alcoholism.” But Naltrexone is not FDA approved to limit, control or extinguish alcohol use at this time.

To make the claim as the author does—“It is entirely possible that rather than going to AA meetings, the majority of alcoholics in the near future can simply carry a bottle of naltrexone with them for drinking occasions”—is foolhardy, irresponsible, and dangerous. Also, it is a wrong interpretation of the state of current research into the use of Naltrexone with alcohol use disorders.

The most positive statement I found about Naltrexone in that regard on the above noted websites was in one of the SAMSHA publications, “Incorporating Alcohol Pharmacotherapies Into Medical Practice.” What follows is that statement:

Naltrexone appears to be effective for attenuating craving in people who are alcohol dependent (Monti et al., 1999, 2001). By blocking craving, naltrexone may enhance the ability of patients to abstain from drinking. By blocking the pleasure from alcohol, naltrexone also may reduce the amount of heavy drinking in those who do drink.

If he wrote the article as a rhetorical device to help people see how medications can be helpful when treating alcoholism, okay.  He accomplished that goal. It had generated 1276 comments as of 10/25/2014 when I last looked. But if he was attempting to give credible information as an epidemiologist on pharmacological treatments for alcohol use disorder, he did not succeed.


A “Cure” for Alcoholism

Stockfresh image by stevanovicigor

Stockfresh image by stevanovicigor

There is an alleged “cure” for alcoholism. Yes, “cure.” It’s called “The Sinclair Method.” It actually encourages individuals to drink, but only after taking naltrexone or nalmefene before they start drinking. Naltrexone and nalmefene are opiate agonists (drugs that blocks opioid receptors in the brain). The theory is their use before drinking will reduce the neurological “reward” after drinking. The “cure” claim is that this reduction eventually leads to the extinction of the person’s desire to drink because they no longer catch the same buzz when they drink.

This is not a joke. The Sinclair Method has its own facebook page; it is promoted in a new documentary, “One Little Pill,” which also has its own facebook page. The original research was done by David Sinclair, and published in the journal, Alcohol & Alcoholism in 2001. You can see the original article here or here. Sinclair believes that drinking alcohol is a learned behavior. Some individuals (partly for genetic reasons) get so much positive reinforcement from drinking, that the behavior becomes too strong for them to control. “They cannot always control their drinking; they cannot ‘just say “no”.’  And society calls them alcoholics.”

The use of the Sinclair Method is said to remove “the neural changes that have caused alcoholism—the over-strengthened pathways of neurons that have developed in the brain, causing alcohol craving and excessive drinking.” The basic premise of the treatment method is that addiction is a learned behavior that has become so entrenched that the addict can no longer control it. “Alcohol drinking produces reinforcement and is learned through that reinforcement.”

Sinclair’s method is the subject of a book by Roy Eskapa, The Cure for Alcoholism. Eskapa said the book’s title means what it says: “Addiction to alcohol can now be cured—not through abstinence, but by always taking a medication an hour before drinking alcohol.” The reduction in cravings is progressive, with the strongest effects in evidence three to four months after beginning to use the Sinclair Method. “The benefits continue increasing indefinitely so long as you take naltrexone if and when you drink.”

Eskapa claimed that the Sinclair Method does not need to be done in conjunction with “extensive counseling.” He based this on his understanding of a study called Project COMBINE. “As a result of this study, naltrexone is no longer just for large clinics specializing in alcohol problems; now, any licensed doctor can ethically and safely prescribe naltrexone for problem drinking.” Citing clinical trials in Finland and the U.S., he said that naltrexone treatment was only effective when it was taken at the same time that alcohol was being drunk. “Until now, most doctors and addiction experts were unaware that to cure alcoholism, one has to drink alcohol while naltrexone is in the bloodstream.”

What the COMBINE study actually found was that all treatment groups experienced a large increase in the percentage of abstinent days, a factor of three times greater. The treatment groups for naltrexone alone, treatment alone and the combination of treatment and naltrexone had comparable outcomes. It did not conclude that treatment wasn’t needed.  What it said was: “Medical management of alcohol dependence with naltrexone appears to be feasible and, if implemented in primary, and other, health care settings, could greatly extend patient access to effective treatment.”

Before you seek out a doctor to prescribe naltrexone (nalmefene is not approved by the FDA for use in the U. S. at this time), let’s look at this alleged “cure.” First, alcoholism is reductionistically conceived as a learned behavior. And the treatment or “cure” is the systematic application of a behavior modification technique known as extinction. Now, the science behind extinction, and the reduction in drinking by using the Sinclair Method is clear. When you positively reinforce a behavioral stimulus, the individual person (or hamster) will do the behavior more. When you stop positively reinforcing the behavior, it will decrease in frequency. This systematic decrease is extinction. Here is a short YouTube primer on the four basic elements of classical conditioning, if you’re interested.

So here’s the kicker. The “cure” is contingent upon continuing the extinction process. In other words, you need to continue taking the medication an hour before you plan to drink . . . forever. But you can resume drinking for the positive reinforcement of the high simply by not taking your pill. So the “cure” is also contingent upon the motivation level of the potential drinker to take the drug before drinking. This is not a “cure” for alcoholism in my way of thinking.

Alcohol in high enough concentrations in the blood stream can cause unconsciousness, stop your breathing leading to cardiac arrest and other physical problems. The physiological effects from alcohol in your blood stream continue to occur even if the neurological reward for drinking is neutralized. The Sinclair Method does not stop these other effects from occurring. It simply neutralizes the reward from drinking and gradually extinguishes the cravings to drink. It does not metabolize the alcohol in your system.

Understanding what is actually treated by the Sinclair Method is slippery. Eskapa’s book title says it’s a “cure” for alcoholism. But he speaks about “alcohol drinking” being positively reinforced to the point that some individuals (excluding those with a genetic predisposition) cannot control their drinking and are called alcoholics.  Alcoholism is more than just a learned behavior or an out-of-control behavioral reinforcement strategy. It’s not something that pharmacological extinction can remove or cure. “It’s like a switch, clickin’ off in my head. Turns the hot light off and the cool one on, and all of a sudden there’s peace”  (“Brick” from: Cat on a Hot Tin Roof).