The Genetics of Opioid Addiction

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The American Society of Addiction Medicine defines addiction like this: “Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors.
Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.” [1]

Like other chronic disorders, risks for developing the disease of addiction are complex, and include genetic and environmental factors.

Opioid addiction is highly heritable, which means the genes we inherit play a strong role in determining who develops this disease. Experts estimate opioid addiction heritability at about 70%, meaning more than half the risk of getting this disease is genetic.

Now let’s talk specifics.

We all have genes that code for the structure and function of the mu opioid receptor. This receptor, when acted upon by an opioid medication, activates cellular events that create pain relief and euphoria. One gene for the opioid receptor is called OPRM1. This gene varies a little bit between people, and the varieties are called polymorphisms, from the Greek for “many forms.” In other words, my gene for the opioid receptor may be different from another person’s gene for this same receptor. Plus, each person has two copies of each gene, so I inherited one polymorphism from my dad and one from my mom, and they could be the same form of the gene or slightly different forms of this same gene. These two forms of the same gene are called “alleles.””

We know that one polymorphism of the OPRM1 gene, called 118A>G, found in around 15% of whites, causes a three-fold increase in binding of endorphins, our bodies’ natural opioids. This gene is associated with an increased risk of addiction to opioids, and variations of responses to opioids.

This means that someone with the AG variety of the OPRM1 gene is more likely to become addicted to opioids, and the sensation that person gets when taking opioids is different from people with other forms of this gene.

Still, association doesn’t necessarily mean causation. We still don’t have enough evidence to say this gene causes opioid addiction, though the gene’s presence is at least associated with opioid addiction.

Let’s turn now to the COMT gene. This gene codes for catechol-o-methyltransferase, which is an enzyme which metabolizes catecholamines in the nervous system.

Catecholamines are the chemicals in the body that are all made from the amino acid tyrosine, and the most common are epinephrine, norepinephrine, and …our old friend dopamine, the pleasure chemical.

Epi- and norepinephrine are the fight or flight chemicals released when we are stressed. Dopamine is the chemical released in the pleasure centers of the brain when we do pleasurable things like eat or have sex. Or use addicting drugs like opioids, nicotine, alcohol, benzodiazepines, cocaine, methamphetamine, or marijuana.

This COMT enzyme inactivates catecholamines including dopamine. Just like the gene coding for the opioid receptor, this gene has different varieties, or polymorphisms. At least one polymorphism is associated with upregulation of mu opioid receptors. Past studies have shown people with this polymorphism need more morphine to treat pain than people without this polymorphism. This difference may also influence the risk of opioid addiction.

Our genetics are not our destiny, however. Certain genes make addiction more likely, but there are others factors that influence risk.

For example, let’s say Jane Doe inherited all of the genes that are associated with increased risk for opioid addiction. Let’s say she got a genetic double whammy, and inherited risky genes from both sides of the family. But Jane grew up in an area where illicit opioids can’t be found. Jane remained healthy, and never had to take opioids in her whole life. Now at age 80, she’s never developed opioid addiction, even though she’s always been at much increased risk than the average person.

Let’s say Jane has a friend named Mary, who inherited all the genes that put her at low risk for addiction. But she was plagued with painful medical problems that required prescription opioids for a few years as a teenager. She also grew up in an area where adolescents had access to a wide variety of drugs including opioids. Because she missed high school often due to her medical condition, she made low grades in school. As a result, she became discouraged with school and started hanging out with drug -using peers. Eventually, Jane started misusing opioids and eventually she developed opioid addiction.

This example illustrates how environmental factors interact with genetic factors to influence risk of addiction, as ASAM pointed out in their definition of addiction.

Let’s remember people face all kinds of environmental and genetic challenges. Stress and negative life experiences increase the risk of addiction. Before we judge someone for having an addiction, let’s remember we don’t know what genetics that person has, or what challenges they’ve faced.

Anyone can become addicted to opioids, given the right circumstances.

1. http://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policy-statements/2011/12/15/the-definition-of-addiction
2. http://www.ncbi.nlm.nih.gov/gene/4988

Addiction

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Sometimes it’s frustrating to hear repeatedly on the news that opioid addiction is such a problem. It’s easy to feel helpless about the situation, and doubtful about how you can help. In this blog entry, I’m going to describe some very specific things you can do to reduce the impact of addiction on our society.

 If you are an addict, get help immediately. Many people have so much shame about becoming addicted that they’re mortified to seek help, fearing the stigma attached to addiction and to an admitted addict, so it takes tremendous courage to admit you have this problem. If you are getting medications from your doctor, tell her the truth. Tell her you are misusing the medicine and need help. She should be able to guide you to an appropriate addiction treatment center, to get an evaluation. At a good treatment center, you should be informed of all of your treatment options. This should include information on both medication-free treatment and medication-assisted treatment.

 If you are doctor shopping for prescriptions, stop it now. As more and more doctors use their states’ prescription monitoring database, sooner or later you will be discovered by one of your doctors. In my state of North Carolina, doctor shopping is a felony, because it’s considered using false pretenses to get a controlled substance. Instead, get treatment. If you’re selling these medications, stop it before you go to jail or kill someone.

 Get rid of all old medication in your cabinets, especially if they are controlled substances like opioid pain pills, sedatives, sleeping pills, or stimulants. According to a recent survey, most young people got their first opioid drug from friends or family. Many times, they took what they found in their parents’ medicine cabinets, or in their friends’ parents’ medicine cabinets. Some communities have regular “drug take back” days, where people bring unused medication for disposal. If you don’t have these in your community, you can wet the pills and mix them with coffee grounds or cat litter, and then throw them in the garbage. The coffee grounds and cat litter will deter addicts looking for medication. Don’t flush pills in the toilet, because there are fears the medication can enter our water supply. (Though I’ve always wondered about drug metabolites that are excreted in urine and feces…don’t they get into the water supply too?)

 Don’t share your medication, with anyone, even family. In this country, sharing medication is so common people don’t realize it’s a crime. Some people feel that if it’s their medicine, and they bought it, they have the right to do with it what they want. This isn’t true. Giving controlled substances to another person is a crime, and dangerous as well. Selling a controlled substance is even worse. Speak up to friends and family, letting them know you don’t think it’s OK for Aunt Bea to give Jimmy one of her Xanax pill because his nerves are bad today. Jimmy needs to see his own doctor.

 Give your children clear and consistent anti-drug messages. Don’t glamorize your own past drug use, including alcohol, by telling war stories. It should go without saying, though I’m going to say it: don’t use drugs with your kids, including alcohol and marijuana. Also, don’t err in the opposite direction, and exaggerate the harms of drug use, because you’ll lose credibility with your kids. Some may remember how the film “Reefer Madness” was mocked. Talk to your kids in an age-appropriate way about drugs and alcohol, even if they don’t appear to be listening.

 If you have a family member addicted to prescription medication, call their doctor to describe what you see. The doctor probably can’t discuss your relative’s treatment, unless given permission, but your doctor can accept information. Write a letter, and be specific with what you’ve witnessed. If your loved one runs out of medication early and then buys off the street, let the doctor know.

 If you feel your addicted loved one is seeing an unscrupulous doctor, report what you know to your state’s medical board. These professional organizations are the best equipped to review a doctor’s pattern of care, to decide if the doctor is prescribing inappropriately. Charts are often reviewed by other doctors who decide if the standard of care is being met.

 Underage drinking is serious. For each year you can postpone your child’s first experimental drug use, including alcohol, you reduce his risk of addiction by around five percent. (1) Don’t involve your kids in your own alcohol consumption; for example, don’t send you kids to the refrigerator to get you a beer. Don’t allow adolescents to drink in your house, fooling yourself with the idea of, “At least I know where they are.” Not only is it illegal, but it’s harmful.

 Don’t use drugs or alcohol to treat minor emotional discomfort, unless you have discussed it with your doctor. For example, don’t use pain pills to help you sleep. Don’t use the Xanax your doctor prescribed for your fear of flying to treat the sadness you feel from breaking up with a boyfriend. Try to get out of the mindset that there’s a pill for every bad feeling, and try to help your friends and family see this, too.

 See a doctor for the treatment of serious mental illness. Some mental disorders are so severe that they require medication. There are many non-addicting medications that treat depression, anxiety, and other mental disorders. Getting the appropriate treatment has been shown to decrease your risk of developing an addiction to alcohol and other drugs.

 Monitor your adolescent’s friends. Youngsters with friends who use drugs are more likely to begin using drugs. Of course, most youngsters who experiment with drugs and alcohol won’t develop addiction, but the younger experimentation begins, the more likely it is that addiction will develop. Older siblings can be a good or harmful influence.

1. Richard K. Ries, David A. Fiellin, Shannon C. Miller, and Richard Saitz, Principles of Addiction Medicine, 4th ed. (Philadelphia, Lippincott, Williams, and Wilkins, 2009) ch.99, pp1383-1389.

Drug Arrest for Doctor

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Last week, news outlets in my area were all aflutter about a physician in a small town who was arrested for prescription medication fraud. It was alleged that he prescribed opioid pain pills to seven of his wife’s friends and acquaintances, none of whom were his patients, so that they could pick up the pills and deliver them to the doctor and his wife.

I’m not giving the name of the doctor, his wife, or the other people arrested, though you can get those if you click on the link below. I figure all of them are getting enough bad press without me piling on too. Besides, this bizarre situation has addiction written all over it. [1]

The SBI investigated this case for four months and finally arrested the eight involved people last week.

The doctor’s wife was a teacher, and she was accused of convincing coworkers at her school to become involved in the illegal activity. These people were teachers, teacher’s assistants, or administrative aides at the school. The illegal prescriptions were filled from late 2012 until early 2014, and totaled around 200 prescriptions and 25,000 doses of hydrocodone. According to the news reports, some of the people filling the prescriptions were using some of the pills, and delivering some back to the doctor and his wife. Others say they thought they were helping people get access to pain pills by using their names.

If this news report turns out to be true, I have a hard time believing the doctor and his wife would take such a risk unless one or both are addicted to opioids. No one is immune to addiction, as we know. And I doubt the people filling the prescriptions would participate in this mess unless they were getting something out of it, too. Claiming to have filled phony prescriptions just to help someone out…I call bullshit on that. These people could also be pill abusers or addicts, or maybe were getting paid to pick up the pills, but I can’t imagine anyone would do this highly illegal thing without some sort of remuneration.

This was a big news story because people were shocked that this drug ring (allegedly) involved a doctor and schoolteachers. But as we know, addiction is an equal opportunity destroyer. For too long, society has imagined that drug addicts are people lying in the gutter with a needle hanging out of their arm. In reality, opioid addicts today look like our next door neighbors.

I reacted to the story with sadness, and with curiosity. I was sad because I think it’s highly likely all the people who were arrested suffer from addiction, and are in need of treatment. But maybe they’ll get lucky, and will be mandated to treatment instead of jail.

I was curious because I wonder why the doctor prescribed only hydrocodone. Why not advance to a more powerful opioid, if you are going to break the law anyway? If you know what you are doing is illegal, why not splurge, and prescribe Dilaudid, or OxyContin? Or maybe he’s smart, thinking that higher powered opioids would call more attention to the scheme. But surely he knew this could not remain secret, with seven other people involved.

This story may illustrate, again, that we don’t do our best thinking in the midst of addiction.

1. http://www.wtvm.com/story/25968161/dr-orrin-walker-abby-walker-rss-bostian-elementary-drug-scheme

Split Dosing

Medication blood level with once-daily dosing compared to split dosing

Medication blood level with once-daily dosing compared to split dosing

Split dosing, when used in reference to the medication-assisted treatment of opioid addiction, means instead of once daily dosing, the total medication dose is divided, or split, into two doses.

Methadone and buprenorphine (Suboxone, Zubsolv, etc.) are long-acting opioids. This property makes them ideal for use in opioid addiction. At the proper dose, both medications relieve physical withdrawal symptoms and cravings in opioid addicts without causing a euphoria or impairment.

When we use these medications for opioid addiction, we prefer to dose once per day. This way, the recovering opioid addict only has to think about taking medication once, rather than using opioids numerous times throughout the day. In active addiction, addicts become accustomed to thinking about opioids frequently; in fact, their whole day narrows into finding opioids, using opioids, and getting ever more opioids. We want to help them break this cycle, and these two long-acting opioids can do this.

However, not all patients will feel normal with once daily dosing of methadone. Patients metabolize methadone at very different rates. Some medical literature says there’s a one-hundred fold difference in metabolic rates of methadone between patients. With methadone, a small percentage of the population metabolizes very quickly, and another small percentage metabolizes very slowly.

This is why methadone induction is dangerous in brand-new patients. Slow metabolizers can accumulate a fatal amount of methadone if such patients are started on too high a dose or increased too quickly.

The activity level of the enzyme that metabolize methadone, the cytochrome P450 3A4, varies a great deal between patients. The activity of the enzyme is thought to be determines by the genetics of each patient. Some patients may metabolize very quickly, with an elimination half-life as short as 8 hours. (Elimination half-life refers to the length of time that it takes for the concentration of a drug to drop to half of its original value in the body). Other patients may have an elimination half- life of up to 130 hours. Most patients average around 36 hours.

Buprenorphine has a consistently long duration of action, of 24-60 hours, with less variability between patients than with methadone. Buprenorphine doesn’t need to be given in split doses when treating opioid addiction, though in some special situations, split dosing may help patients.

Patients who need split dosing are given part of their dose in the morning and part of their dose to take later, as close to 12 hours later as they can manage. Since many opioid treatment programs (OTPs) are set up to dose once per day, in the morning hours, patients who split dose are given half to two thirds of their total dose at their OTP. The other half to one third is given to the patient as a take- out dose for later that day.

We decide which patients need split dosing by listening to their symptoms. During induction, we know the patient’s dose isn’t high enough to last the whole day, so the need for split dosing can’t be determined until later in treatment. Patients who are fast metabolizers often get to 120mg or more, yet feel opioid withdrawal late in the day. Or they may feel drowsy after dosing but feel withdrawal later in the day. These patients may be fast metabolizers.

Before I can order split dosing, I need to get permission from the state and federal authorities, just like I would for extra take homes doses for patient emergencies. In my state, methadone peak and trough levels are usually requested before they grant permission for split dosing. We draw the patient’s blood three hours after their dose, which is the peak. That’s the highest blood level the patient will have on that dose. On the next day, right before they take the next day’s dose, we draw another methadone blood level, called the trough, which is the lowest level the patient ever has on that dose.

Then we compare the peak to the trough. If the peak is more than twice the trough level, the patient is probably a fast metabolizer who will feel better taking part of their dose in the morning and part in the evening.

Pregnant women, particularly in the last trimester of pregnancy, may do better with split dosing. It’s common for methadone metabolism to increase during pregnancy. Blood levels also drop during pregnancy due to plasma volume expansion and other factors, so that a given dose gives progressively lower blood levels as the pregnancy proceeds. Also, studies have shown the fetus is less affected by methadone when the total is divided into two doses.

However, the woman’s home environment and other factors must be considered before ordering split dosing. For example, if the pregnant patient is living with a partner in active addiction, that partner may bully the woman into giving him her second dose. If the pregnant patient is struggling with other drug use, splitting the dose may be too risky.

Some medications induce the metabolism of methadone, meaning the metabolism speeds up. The total dose can be increased to compensate for this, but sometimes the effect is so pronounced that the patient needs to change to split dosing to feel normal.

Every time I order split dosing, the nurses become wary. That’s because the proper way to start split dosing is to give the patient’s usual entire amount first thing in the morning on day one. Then, a take home for half the dose is given to the patient to take home for later use that first day. The nurses worry I’m going to overdose the patient. Starting with day two, the patient gets a half dose in the morning and a half dose in the evening.

If you don’t start the day with a full dose, but rather start on day one with half in the morning and half in the evening, the patient will start off in withdrawal, and can de-stabilize for the first four or five days.

Instead of giving half the dose in the morning and half twelve hours later, I sometimes give two thirds in the morning and one third at night.

Dosing of both methadone and buprenorphine can be split for better control of pain. Even though opioid treatment programs’ primary purpose isn’t to treat pain, many patients have both opioid addiction and chronic pain.

The analgesic, or anti-pain, effect of a dose of methadone or buprenorphine lasts for about six to eight hours. That’s why I warn opioid addicted patients with chronic pain that dosing daily may help with pain in the morning hours, but not in the evening or nighttime. I don’t want to mislead them in their expectations for treatment.

If a patient is doing very well in treatment, has no illicit drug use, is making good progress in their recovery, but still has disabling chronic pain, I’ve asked the state and federal authorities for permission to split dose the patient for better pain control. Sometimes it works great, and sometimes it doesn’t help at all.

Before considering split dosing, I have to look at the patient’s overall situation. A patient being considered for split dosing is at an opioid treatment program for a reason: she has lost control over her use of opioids. It may not be realistic for me to expect this patient to be able to appropriately manage a take home dose until/unless this patient has had time to make progress in her recovery. I do want to get the patient on a dosing schedule that helps her feel normal, but I also want her to be safe.

New Buprenorphine Product: Bunavail

Manufacturer's ad

Manufacturer’s ad

Until this month, only buprenorphine in the sublingual form was FDA approved for the treatment of opioid addiction. This includes commonly known brands like Suboxone and Zubsolv, and generic buprenorphine both with and without naloxone added.

But earlier this month, the FDA approved Bunavail (B-YOU-na- vail), a buprenorphine product that is absorbed through the mucosa of the cheek. This method of delivery is termed “buccal.” The company making Bunavail says the product has an adhesive, which they call “BioErodible MucoAdhesive,” that improves absorption through the cheek mucosa. This product has twice the bioavailability of Suboxone film, and that’s the selling point for this new product.

Bioavailability is the percent of the drug that is absorbed into the bloodstream out of the total amount of the drug that is administered. If a drug is injected, by definition it has 100% bioavailability. Other routes of administration have less than 100% bioavailability because not all of the drug is absorbed orally, or due to the first-pass metabolism seen with some drugs like buprenorphine. When using a route of administration with lower bioavailability, more of the drug must be given to achieve the same blood level as when the drug is injected.

Buprenorphine has poor gastrointestinal availability. If a drug company made an oral tablet to be swallowed, less than 10% of the drug would be absorbed into the bloodstream. Sublingually (under the tongue), bioavailability of buprenorphine is said to be anywhere from 30 to 50%, and can be influenced by things like the pH of oral secretions (an acid environment interferes with absorption, which is why we tell patients not to drink any soft drinks, coffee, or tea for fifteen minutes prior to dosing).

So what does Bunavail’s higher bioavailability mean on a practical level? Bunavail’s films contain less buprenorphine than Suboxone, but deliver the same blood level. And if the blood level’s the same, the effect of the drug is the same. In other words, individual patients should feel the same.

Other than that, I can think of a few potential advantages. With higher bioavailability, fewer grams of buprenorphine would be prescribed, and fewer grams of buprenorphine that could make it to the black market.

Since less of the drug is needed per unit dose, perhaps the price will be lower. I have no information about the costs of this new product…but I’m going to make a wild prediction that Bunavail won’t be significantly cheaper than Suboxone. Zubsolv has higher bioavailability but I don’t think it’s significantly cheaper than its competitors.

The makers of Bunavail are making a big deal about the inconvenience of sublingual forms of buprenorphine compared to their new product, which sticks to the side of the cheek. In an interview on Bloomberg News, one of their scientists said patients taking Bunavail can talk and swallow while their medication is dissolving, something that can’t be done with their sublingual competitors.

OK, maybe that’s an advantage…but what are we talking about, five or ten minutes at most? I don’t know if patients will think that’s a big selling point, but time will tell.

On their website, the manufacturers caution, “Do not switch from BUNAVAIL to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of BUNAVAIL is not the same as the amount of buprenorphine in other medicines. Your doctor will prescribe a dose of BUNAVAIL that may be different than other buprenorphine-containing medicines you may have been taking.”

To me this means I will have to be careful if I have a patient who wishes to switch buprenorphine products. However, the package insert says that 4.2/.7 mg of Bunavail is equal to Suboxone 8mg/2mg. The package insert goes on to say that patients should be started at 2.1mg and increased in increments of 2.1mg until a maintenance dose of 8.4mg is reached, though patients may go as high as 12.6mg

The insert also says not to tear or cut the film. Manufacturers of Suboxone say the same thing about their film, though cutting those films is fairly standard practice. I think that since the drug company hasn’t done any testing of their products when cut or torn, they can’t say for sure that it’s OK.

The company behind Bunavail, BioDelivery Sciences International Inc. (BDSI) has several other unique products. For example, they already market Onsolis, which is fentanyl also in a buccal (absorbed through the cheek) film. They’re also in phase 3 trials now with another buprenorphine product that uses the special mucoadhesive they developed, but it will be marketed for moderate to severe chronic pain. No information is available yet regarding the doses contained in this product.

Bunavail is expected to be marketed to doctors the last quarter of this year.

Naloxone Controversy

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It’s a misleading title, because most people support naloxone use. At this point…there’s not much controversy. Unless you live in Maine.

Their governor, Paul LePage, vetoed a bill, passed by their State House in 2013, that allowed naloxone to become more widely available. He called the life-saving medication and “escape,” and “An excuse to stay addicted.”

Naloxone is an escape in a way – an escape from death.

However, before learning about naloxone, I had some concerns too. For example, would having naloxone available for an overdose encourage people to use more illicit opioids? Would addicts be more likely to push then envelop of safety in the quest for the ultimate opioid high?

The answer appears to be no, at least according to some small studies. One of them was a study of intravenous heroin addicts in San Francisco, who received an eight-hour training in how to prevent heroin overdose, how to give CPR, and how to administer naloxone. [1]

These twenty-four study subjects were followed prospectively for six months. These addicts witnessed a total of twenty opioid overdoses. All of the overdose victims were said to be cyanotic, unresponsive, and have no respirations. The addicts in the study, who had received the eight hour training, administered naloxone to 75% of the overdose victims they encountered. They performed CPR on 80% of the overdose victims, and 95% of the overdose victims had one or the other of the two interventions performed. All of these overdose victims survived.

The study did not show an increase in the incidence of opioid overdose. In fact, the addicts in the study used less heroin over the study period, even though no part of the study was dedicated to encouraging the reduction of illicit opioid use or to entering addiction treatment.

Granted, the study participants had to be motivated in order to spend eight hours doing the training, so maybe they were already motivated to cut down or stop using drugs. But on the other hand, about half of these study subjects were homeless, a demographic many in our society would assume is poorly equipped or motivated to help anyone else. Yet they demonstrated a remarkable willingness and capability to help peers dying from overdoses.

Emergency medical services were called in only two of the overdoses. When study subjects were asked why they did not call emergency medical services, half said it was due to fear of police involvement and arrest. Twenty-five percent said no phone was available, and 25% said they didn’t see a need for EMS.

This information underscores the importance of Good Samaritan laws. In the broadest sense, Good Samaritan laws protect a person who tries to help another person from civil or criminal penalties.

Initially these laws were passed to protect doctors from being sued if they attempt to save the life of someone who is not a patient. For example, if I witness a man choking to death in a restaurant and I rush over to do the Heimlich maneuver, I can’t be sued if I break his ribs in my effort to get him to hack up the meatball wedged in his trachea.

Good Samaritan laws, as they apply to drug overdoses, give some degree of immunity to people who try to intervene to save another person’s life from drug overdose.

For example, in my state, our Good Samaritan law says if a person seeks medical assistance for an individual suffering from a drug overdose, that person will not be prosecuted for possession of less than one gram of cocaine or one gram of heroin. The bill has provisions for doctors to be able to prescribe naloxone to any person at risk of having an opioid-related overdose. Doctors can prescribe naloxone to the friends or family members of a person at risk for an overdose, even if that person is not a patient of the doctor. This is called third-party prescribing; the law hacks through red tape of previous regulations that said doctors could only prescribe naloxone for their own patients. And our Good Samaritan law says a private citizen can administer naloxone to an overdose victim, and so long as they use reasonable care, will be immune to civil or criminal liability.

Not all states allow third-party prescribing of naloxone or even Good Samaritan laws. Look on the map at the top of this blog, and if you live in a state that hasn’t yet passed these laws, write your congressmen. This is such an important issue, and naloxone needs to be more widely prescribed. (I don’t know why Maine is colored on the map as if they have naloxone laws).

Who should get a naloxone prescription? Opioid addicts should obviously receive kits, and the friends and family members of these addicts. I believe it should be considered for any patient prescribed opioids, including patients on opioids for chronic pain, and patients prescribed methadone or buprenorphine to treat opioid addiction.

Kits should certainly be provided for high-risk patients – opioid addicts recently released from jail or detox units.

I wish I could prescribe kits for all of my patients on methadone or buprenorphine now, but aside from the program where I work in Wilkes County, it’s not yet easily available.

But it will be soon. In April 2014, the FDA approved a commercially available naloxone auto-injector marketed under the name Evzio. This kit, which delivers .4mg of naloxone intramuscularly or subcutaneously, has both written and voice instructions. Each kit contains two doses, and it can be administered through clothing. This kit should be available in pharmacies this summer.

Until then, there are other options. Doctors can call a local pharmacy to see if they would be interested in making a kit for sale to patients. At a minimum, it would include one or two vials of naloxone, a needle and syringe, rubber gloves and alcohol wipes to cleanse skin prior to injecting. This would be a relatively cheap kit to make, but questions persist about who would pay for it: the patient, their health insurance company…
The Harm Reduction Coalition has been instrumental in providing intramuscular naloxone kits to anyone who wants one. They have contacted OTPs in my state to ask if they can hand out kits and other information, so that’s another possible source for a kit. If you are reading this article and want a naloxone kit for either yourself or a loved one, please contact either the Harm Reduction Coalition at: http://harmreduction.org
This wonderful organization does other good works besides distributing naloxone kits, and it’s worth checking out their website.

At the opioid treatment program where I work in Wilkes County, NC, Project Lazarus has paid all or part of the cost of intranasal naloxone kits for our patients who enter treatment. Thus far I know of three lives saved by these kits. None of them were our patients; our patients used their kits to save other people.

I’ve written about Project Lazarus before in my blog. This organization, founded by Reverend Fred Brason, has implemented ongoing measures that reduced the opioid overdose death rates not only in Wilkes County, but probably statewide as well. Other states have started programs modeled on Project Lazarus. You can go to this website for more information: http://projectlazarus.org I know that in the past, Project Lazarus has been willing to send a naloxone kit to anyone who has a need for it, so that’s another possible source for a kit.

I predict it will become easier to get relatively cheap naloxone kits from pharmacies everywhere as the momentum behind naloxone availability grows.

1. Seal et al, “Naloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: A pilot intervention study,” Journal of Urban Health, June 2005; 82(2): 303-311.

Naloxone

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Medical journals, news outlets, and the internet have been exploding with new articles about naloxone. As awareness of this opioid overdose antidote grows, more people are pushing for this drug’s wider availability.

I’ve posted blogs about how the Project Lazarus kits have saved lives in my Appalachian corner of the world, but now let’s review some of the science behind naloxone.

Naloxone is an opioid antagonist, which means the drug binds to the mu opioid receptors in the brain, but instead of stimulating these receptors to produce euphoria and pain relief, naloxone does the opposite. It occupies the receptor and prevents opioids from attaching to these receptors to cause euphoria and pain relief. Naloxone has a high affinity to the mu opioid receptors, meaning it sticks like glue to them, but it does not activate these receptors.

If you give naloxone to an average person with no prior opioid use, not much will happen. Because naloxone can block our body’s own opioids, endorphins, that person might feel a little achy, tired, and irritable. But for the most part, when naloxone is given to a non-user of opioids, nothing happens.

If the patient has used opioids just once, recently, the patient won’t have withdrawal when given a dose of naloxone, since the body isn’t used to having opioids anyway. Naloxone in this case restores the body to its usual state. This’s why naloxone can be useful in a patient given opioids for surgical anesthesia. After the surgery is over, doctors can use naloxone to reverse the opioid anesthesia if they want the patient to wake up more quickly.

But in a patient with opioid addiction (or in a chronic pain patient) who uses opioids daily, naloxone causes opioid withdrawal. With long-standing opioid use, the body makes adjustments to counteract the chronic presence of opioids. When these opioids are whisked away with naloxone, this balance is abruptly upset, and the patient goes into precipitate withdrawal, if enough naloxone is given.

Naloxone is the opioid buzz-kill drug… and it’s also the opioid overdose life saver.

People die from opioid overdoses because the brain gets saturated with opioids. The part of the brain that tells us to breathe during sleep, the medulla, also gets saturated, and eventually shuts off. This usually occurs gradually. The respiratory rate slows over one to three hours, until all respirations stop. Then tissues of essential organs like the brain and heart die from lack of oxygen.

If naloxone can be given during this process, the opioids are tossed off brain receptors, and the medulla fires urgent orders for the body to resume breathing. The patient wakes up, so long as irreversible damage hasn’t yet been done to the brain and heart. In some cases, the patient goes into full precipitated opioid withdrawal, but usually the naloxone doesn’t reverse all of the opioids on board, just enough to save the patient’s life.

It’s a dramatic event. I’ve seen this in the emergency department during my Internal Medicine training. A patient can be lying on a stretcher, dead… then one dose of naloxone…. and they are sitting up, asking what happened to them. And sometimes they vomit. That’s another thing I learned in training. After giving a dose of naloxone, take one step back. Even better, place the patient in the “recovery position,” illustrated at the top of this blog, so that if they do vomit, they won’t aspirate the stuff into their lungs.

Naloxone is a relatively cheap drug, and it can be administered in several ways: intravenously, as doctors and EMS workers have always done, intramuscularly, subcutaneously, and intranasally.

Project Lazarus uses this last method. Their overdose kits contain two vials of naloxone 2mg each, and are in a syringe with a nozzle that is attached to the end of the syringe. This causes the medication to spray when the plunger of the syringe is pushed. It’s sprayed up in the nose of an unconscious person, and gets absorbed quickly. In fact, the response rates of all methods of naloxone administration are about the same – two to three minutes. If the patient doesn’t respond after a few minutes, the second dose can be given. Or if the patient initially responds but then gets sedated again, the second dose can be given.

The Harm Reduction Coalition gives out kits with a vial of naloxone and a 3cc syringe and needle. It takes some skill to administer naloxone intravenously, but this kit can be used intramuscularly or subcutaneously. All the rescuer has to do is draw the medication from the vial into the syringe, then stick the needle into the thigh muscle and push the plunger. Usually that delivers the medication into the muscle, unless the person has a great deal of fat between the skin and muscle. But that doesn’t matter, since this medication also works when injected into the subcutaneous tissue.

Each version of a naloxone kit has its advantages. The intranasal kit doesn’t require a needle, so there’s no risk of an accidental needle stick by the rescuer. But it’s a little more expensive. The intramuscular kits are really cheap, but some people in the community worry about handing out a needle and syringe that could be used to inject drugs. I don’t worry about that, since needle exchange should be done in every community, but that’s a bit of a tangent. More practically, addicts don’t use 3cc syringes; they’re too large. Addicts would miss their shot, and too much of their drug of abuse would get left behind in that big syringe.

I don’t think it matters what kind of kit is made available to addicts, their families, and first responders. We just need to get some kind of naloxone kit to these people.

Of course, all these kits contain the recommendation to call 911 immediately. But those precious minutes before EMS arrives may mean the difference between life and death. If naloxone can be given, the patient may be saved. Their brain function may be saved.

To be continued…

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