TL neuro

April 30, 2019

Obtaining the Opioid Overdose Rescue Medication Narcan “Over the Counter” Isn’t Simple

Filed under: Drug Overdose, Opiates — mtaffe @ 11:12 am

The news is full of accounts of the opioid crisis, most pointedly on deaths and near-lethal overdose events. There has been a long and steady increase in opioid-related deaths as depicted on graphs like this one from the CDC. The trend started in 2000 and mostly involved prescription opioids such as oxycodone and hydrocodone. These deaths stayed elevated increased less quickly in the past decade. Unfortunately, deaths associated with the non-prescription illicit opioid heroin started to increase in 2010, eventually reaching the levels associated with prescription opioids in 2016. Despite this long and steady increase in opioid-related deaths (and other indicators of harm were in parallel to this, ranging from epidemiological evidence of non-medical use to a demand for addiction treatment), it took until the recent Phase 3 to gain broad media and political attention. This more recent phase has been characterized by a rapid increase in deaths associated with highly potent synthetic opioids- most commonly fentanyl and, occasionally, derivatives of fentanyl. Much of this appears to be driven by illicit drug suppliers using fentanyl as a boosting agent without actually informing users that they are getting fentanyl. Fentanyl, and related derivatives, are popping up in association with heroin, in pressed pills faking the appearance of prescription opioid products (like Oxycontin) and in other non-opioid drugs such as cocaine. In September, my neighborhood had a small cluster of opioid-related overdoses (including 3 fatalities and 2 survivals) from an adulterated cocaine supply.

Although it took far too long to gain traction with first responders, there is an antidote to opioid overdose that can be helpful in preventing deaths. It is the compound called naloxone, which is an antagonist (blocker) of the mu opioid receptor. This is the brain receptor that is most involved in the respiratory suppression effects of opioids that leads to overdose deaths. If an individual who is intoxicated with an opioid is given a dose of naloxone, it can prevent death all by itself or it can slow the respiratory effects long enough to bring additional medical interventions to bear.  The wikipedia article reminds us “Naloxone was patented in 1961 and approved for opioid overdose in the United States in 1971“. So what’s the problem?

Availability. By the time anyone in the vicinity notices that a person is in respiratory suppression subsequent to their opioid use, this person may not have a lot of time before death. It may take time to get emergency services to the person or the person into the emergency room. There may not be anyone around who cares to intervene beyond calling 911. Which means that equipping first responders (EMS, firefighters, police) with an easily administered version of naloxone is a key component. This has been gradually accomplished with the Narcan nasal spray. There was resistance. In the waning years of the Bush administration there was still resistance to the idea of equipping first responders but this changed a lot during the Obama administration (overview from health affairs). First responders can only do so much, so in parallel there have been efforts to get Narcan into the hands of private citizens so that they can intervene in a suspected overdose. Naloxone by itself has minimal to no effects on an otherwise healthy individual and will not increase health problems brought about by overdose on many other non-opioid drugs so the dangers of a false alarm good Samaritan dosing with Narcan are pretty minimal. Many states have taken action to allow Narcan to be sold without a prescription and the major pharmacy chains Rite Aid, Walgreens and CVS have stepped up to provide this service. So the antidote is “available” to anyone. The next phase is to get this into more people’s medicine cabinets, just in case. And I am writing up my experience, below, to show you why this medication is not truly “over the counter” in the way you expect and why it is a good idea for you to go out and get it. Apparently it has a 12 month expiration date and is probably still highly effective for 18-24 months and even expired Narcan is probably better than no intervention when someone is overdosing on an opioid.

My experience obtaining “over the counter” Narcan.

I had been meaning to secure a Narcan kit for my medicine cabinet for a few years and just never go around to it. I’m a parent of teens and a friend and neighbor to other parents of teens. Teens, as they do, have a chance of coming in contact with opiods, of using opioids and of being around other kids who are using opioids. Intentionally or, as we saw in the fatalities in my neighborhood in 2018, unintentionally due to contamination of other drugs with fentanyl. And the surgeon general issued an Advisory reminding us that “You have an important role to play in addressing this public health crisis“. So I went down to my local CVS and tried to obtain a nasal Narcan kit.

The first thing to understand is that it is not “over the counter” like ibuprofen or condoms. You have to go to the pharmacist and ask for it. I did so and it was clear to me that this was the first time this particular pharmacist had dealt with the process. She was informed and super great about it but it was not a familiar process. She had to first print out some warning / informational page. This took time and made me wonder why they don’t print out a few and stick them under the supply on the shelf. I don’t think I would have had to show identification but I am not entirely sure, I was there for sudafed and had already shown it to her for that purpose.

What I did find out is that one has to be 18 years of age or older to purchase. This is a problem and a big one, if you ask me. Teens are a clear risk group and their peers should be able to obtain Narcan. As a related issue, I was informed it would be $130 for the two-dose nasal spray kit. No big deal for me, but you can imagine that this may be a HUGE barrier for kids or for street / homeless people. These are details you will want to check in your local jurisdiction because I would not be surprised if there are significant variations in the state laws and differences across drug store / pharmacy chain policies. Teen access and cost are barriers in my city, making it even more important in my view for parents to obtain the Narcan, put it in their medicine cabinet and tell their teens where it is and how to use it. It may help to review a youtube video on what overdose looks like (such as this one). I even made my kid take it to Coachella and there was very little fussing about that. It doesn’t have to be some huge thing, just a recognition that stuff can happen and it is better to be prepared.

Okay, back to the pharmacy process. I was told they have to “treat it like a prescription” in their system. Okay, no biggie for me but could be a little off-putting for teens, homeless and the illicit drug using community generally. The pharmacist asked me three questions- did I use drugs (no), was I in contact with anyone using drugs (I said no since I wasn’t thinking of some specific person) and a third similar question I can’t recall but also answered “no”. The pharmacist next informed me that she could not sell me Narcan if I answered no to all three questions. Which is another barrier- apparently the CVS policy in my city is to not sell it to anyone for ill defined general prophylaxis safety reasons. This was of course my actual reason. So I said “whoa, whoa, back up, I’ll give you a yes on the second question”. Okay phew, back on track. I was next asked “What is the name of this individual?” WHAT? As you can see, this is another huge barrier to the way Narcan is provided “over the counter”. At least in my city / state and at the CVS pharmacy. Again, YMMV in your location.

As I said the pharmacist was totally helpful. She fully realized what I was doing and did not give me any static when I reversed my “no” to the second question and answered her person query with “John Doe”. She did ask for an address (!) which I made up from the surrounding streets- I don’t know what would have happened if she had entered an address that didn’t exist. I also had to give a phone number for this person! I also made that one up but… the final stages of the process  got queried about text messages and it was clear that I’d accidentally made up a phone number that was already in the CVS database for a real customer. The pharmacist kindly deleted the phone number from the record.

I eventually walked out with a Narcan kit. $130 poorer and about 30 minutes after starting the process. There was no line at the pharmacy that particular day but it would not be unusual to be waiting in line. This is not a process that facilitates a rapid response to an overdosing individual.

You can see, that in addition to the time it takes, all of the process to obtain Narcan that I experiences presents several barriers. A person seeking Narcan under the stress of an overdosing friend might simply walk away if they didn’t have the money, weren’t 18 yet or were scared off by the requests for information on the victim and didn’t think to lie. For all I know this particular pharmacist was cool but another one might get sticky about my obvious lying with respect to the “John Doe” that they needed to enter as the patient in their database for the sale.


Additional Reading: Dose Makes the Poison blog fentanyl archive.

June 22, 2018

An oxycodone vaccine prevents the acquisition of self-administration

Filed under: Opiates, Vaccines — mtaffe @ 2:59 pm

A paper from the laboratory has recently been accepted for publication .

Nguyen*, J.D., Hwang*, C.S., Grant, Y., Janda, K.D.. and Taffe, M.A. Prophylactic vaccination protects against the development of oxycodone self-administration.  Neuropharmacology, 2018, 138:292-303. [ Publisher Link ][ Free Author Share ]

This paper reflects joint effort with members of the Janda laboratory in our ongoing collaboration [ related posts ] to evaluate their anti-drug vaccines for efficacy in rat models of drug exposure and abuse. In this study we focused on a vaccine that induced antibodies that bind to oxycodone and evaluated the efficacy of this active vaccine (Oxy-TT) versus the carrier protein tetanus toxoid (TT). Our primary goal was to examine the intravenous self-administration of oxycodone in the rats.

This reorganization of Figure 2 from the paper depicts one of the key findings. The right panel shows the average number of infusions of oxycodone (0.06 mg/kg/infusion) obtained by subgroups of the Oxy-TT and TT rats. This median split analysis divides the Upper from Lower halves of the distribution based on average oxycodone responding across the 18 session acquisition interval. The distribution for the Oxy-TT group was more bimodal compared with the TT control group, indicating that some Oxy-TT rats took very little oxycodone across the acquisition period and some self-administered more. We defined successful acquisition as an average of 7 or more infusions obtained across two sequential days and the left panel reflects the proportion of the entire distributions of TT versus Oxy-TT that met this standard. Combined, we can infer that about 40% of the Oxy-TT animals essentially failed to acquire stable self-administration behavioral whereas all of the TT group did under these conditions. While it may seem disappointing to some eyes that the vaccine “worked” to prevent the establishment of stable self-administration in only 40% of the animals, this needs to be viewed in the context of human substance abuse. Only minorities of the individuals who try a given drug will go on to develop a habitual use pattern. This can be observed (cross-sectionally) in the Monitoring the Future data [vol 1 adolescents; vol 2 adults], in Schramm-Sapyta et al 2009 and in Anthony et al, 1994. The best way to reduce harm from repetitive use problems with drugs is to prevent it from progressing to this stage in the first place. Our study shows that the Oxy-TT vaccine is potentially capable of protecting a substantial subset of those individuals who sample a drug enough to become habitual users.

These panels from Figure 5 of the paper show that there was basic biological efficacy of the vaccine. These data show the plasma (left panel) and brain (right panel) amounts of oxycodone in the two vaccine groups after administration of 1.0 or 2.0 mg/kg subcutaneously. This shows that considerably more oxycodone is in the plasma of the Oxy-TT groups (as is expected since the antibodies should retain drug in the bloodstream and not let it get into other tissues. Lesser amounts of oxycodone were in the brains of the Oxy-TT group as well which is again consistent with the anticipated effects of successful anti-drug vaccination.

The second major behavioral finding is a bit more subtle. As you can see from the first figure, above, the Oxy-TT rats that did acquire self-administration responded for more drug than did the TT control animals. This is consistent with the second figure, i.e., that less of each infusion of drug was reaching the brain. Thus, assuming the rats on average seek the same approximate amount of drug in their brain, the vaccine resulted in an increase in self-administration behavior. In order to probe the extent to which the rats prefer to self-administer oxycodone we increased the workload. In training the rats only had to make one lever response for each infusion of drug, known as a Fixed Ratio 1 (FR1) contingency. But the Progressive Ratio procedure makes each successive infusion within the daily session cost more. When we did that, the Oxy-TT animals decreased their intake to a greater extent than did the TT rats. This figure is from a second cohort of rat groups that were trained to self-administer a

higher per-infusion dose (0.15 mg/kg/inf) of oxycodone. Under these conditions the Lower half of the Oxy-TT group self-administered about the same amount of drug as the entire TT group and the Upper half self-administered more. The figure depicts mean intake, post-acquisition, in four different workload conditions, starting and ending with the FR1 training condition. The two middle bars depict the oxycodone intake under two PR schedules which differ in steepness of the incrementing workload. There was a change for the TT group only in the hardest PR condition but this did not reach statistical significance. In contrast the overall number of infusions in a session that were obtained by the Oxy-TT animals (this is for the entire group) were reduced when it took more responses to obtain successive infusions. This shows that despite self-administering slightly more oxycodone when it is easy to get (FR1), the Oxy-TT animals are more likely to reduce their intake when the conditions are made slightly more difficult. Making drugs more difficult to obtain is, of course, one of the population level strategies we use to combat drug addiction. This is reflected in taxes and the regulation of sales of alcohol and tobacco that have been proven to reduce problematic use of these legal substances. Parents routinely use different strategies to make it more difficult for their teenagers to access drugs of all types. Many therapeutic interventions for drug abusers involve lifestyle changes that make getting access to drug more laborious. Thus, a strategy that makes an individual more liable to reduce their drug use when the costs increase has the potential for success in reducing drug use harms.

This last finding also has important implications for the design of human clinical trials that attempt to test the efficacy of anti-drug vaccines. The default approach has been to use measures of drug use as the measure of “success” of the trial. These data suggest that vaccinated people could use the same or even slightly more drug and still be getting a protective effect. That is, they might become more susceptible to other interventions which, for example, raise the cost or effort of getting drug.


*authors contributed equally

Funding for this work provided by USPHS Grants R01 DA035281, R01 DA024705, UH3 DA041146 (K.D.J.) and F32 AI126628 (C.S.W.).

March 3, 2014

Misuse of Prescription Opioid Medications

Filed under: Drug Overdose, Opiates — mtaffe @ 11:50 am

CDC-allopioidODsThis post will initiate a new conversation on this blog about the detrimental health effects of the non-medical use and misuse of prescription opioid medications such as Oxycontin, Vicodin and Percocet. The overdose death of beloved US actor Phillip Seymour Hoffman recently re-focused attention on prescription drugs. Mr. Hoffman had reported in 2013 that he had relapsed to heroin use subsequent to a prescription drug use episode. This, after a 23 year interval of recovery from drug use in his 20s.
It isn’t made specifically clear that Mr. Hoffman’s 2013 relapse was with prescription opioid analgesics and the autopsy report after his death reported he was taking benzodiazepine medications in addition to heroin. Nevertheless, this case echos a recent trend for an increase in prescription opioid overdoses in the general US population. Data from the CDC (obtained in this case from a NIDA site) show the increase in unintentional overdose deaths from 1999-2008.

Subramaniam-teenadmissionsA meeting report by B.M. Kuehn (2010) illustrates data sourced to G. Subramaniam showing an increase in prescription opioid treatment admissions for adolescents over a similar interval. This trend for adolescents is reflected in broader data reported by the Treatment Episode Data Set for all people 12 and older. This post outlines and graphs the relative increase for prescription opioids which reached 8.6% of all admissions in 2010 following a steady increase from about 1999 onward. In contrast admissions for stimulant treatment were in decline from 2006-2010 and heroin-related admissions were approximately stable from 2000-2010.

There are other data sources available which point to a very clear picture. The extra-medical use and abuse of opioid medications has been growing for nearly 15 years in the US. This has led to clear implications for health, including dependence and overdose deaths. A recent paper by Cicero and colleagues indicates that medications that contain oxycodone and hydrocodone are highly preferred in individuals that are opioid dependent. Recent papers from Mars and colleagues and from Young and Havens show that most young users of heroin had a prior history of extra-medical use of prescription opioids. Thus the downstream impact of prescription opioid misuse may extend to individuals who are no longer using prescription medications as their primary substance of abuse.

The lab has recently begun a new NIH funded project on prescription opioids: R01 DA035281

December 20, 2012

Anti-drug vaccine explainer animation from NIDA

Filed under: Cocaine, Opiates, Vaccines — mtaffe @ 8:58 am

There’s also a writeup of the Koob/Janda/Crystal collaboration to generate an anti-cocaine vaccine with adenovirus carrier protein and the Koob/Janda work on heroin vaccine.

Wee, S., et al. Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects. Neuropsychopharmacology [Epub ahead of print September 14, 2011]. PubMed

Stowe, G.N. et al., A vaccine strategy that induces protective immunity against heroin. Journal of Medicinal Chemistry 54(14), 5195–204, 2011. PubMed

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