Incident Atrial Fibrillation and Intoxicants

I remain very interested in the cardiac and brain complications of medications and substances that are commonly used to get high or create altered states.  I am also very interested in the popular trend to characterize cannabis as some previously undiscovered medication that can cure everything ranging from anxiety to obstructive sleep apnea.  I was naturally interested when I saw this paper (1) looking at the issue of incident atrial fibrillation and common intoxicants.

The authors examine a very large database in California that included anyone who had been seen in an emergency department, ambulatory surgery center, or hospital over a period of 10 years (2005-2015).  After they eliminate minors, subjects with persistent atrial fibrillation, and subjects with missing data they had a total of 23,561,884 people. 998,747 of those people had incident atrial fibrillation (defined as the first encounter for atrial fibrillation).  Since their study design is a retrospective observational study they also recorded substance use was considered present if Substance use was considered present if there was coding for any indication of use of methamphetamine, cocaine, opiates, or cannabis.  Knowing the atrial fibrillation and substance use diagnoses – the authors calculate the hazard ratio for each of the substances of interest.

Hazard ratios are basically the ratio of the people exposed to intoxicants who developed atrial fibrillation over the unexposed who developed atrial fibrillation.  So any number greater than 1 means that the population exposed to intoxicants had greater risk.  The corrected hazard ratios were noted to be 1.86 (methamphetamine), 1.74 (opioids), 1.61 (cocaine), and 1.35 cannabis. The authors adjusted for common atrial fibrillation risk factors and ran an additional negative control analysis and looked at the scatter of data pints for these 4 substances and hazard ratios of developing appendicitis, connective and soft tissue sarcoma, and renal cell carcinoma and showed no consistent pattern for these illnesses.

There are a couple of interesting considerations relevant to this study.  The first is the mechanism of action in each case. With stimulants there is a direct hyperadrenergic effects and depending on the individual and dose of the drug varying degrees of tachycardia, palpitations, and hypertension.  Long term users frequently end up with cardiomyopathy from these effects and in some cases ventricular arrhythmias and congestive heart failure. There can also be acute vascular effects like ischemia either due to the increased cardiac demand or pre-existing arteriosclerosis. Atrial fibrillation has not typically been placed in that group of morbidities from stimulant use. Patient with atrial fibrillation often notice emotional precipitants for discrete episodes or atrial fibrillation although a recent study showed that the only reliable precipitant was alcohol use (2). There were significant limitations with that study with attrition and length of the study although I generally agree that alcohol is a clear participant.  Precipitants need to be carefully approached and I suspect that attentive physicians have noted variable phenomenology on an individual basis. 

The high hazard ratio for opioids is a little puzzling. Hyperadrenergic states can occur with the euphorigenic effects and withdrawal effects as well. Direct comparison with stimulants may be difficult due to rapid dose escalation and some degree of tachyphylaxis.  Cannabis is not surprising to me at all. Many initial cannabis smokers notice that their heart is pounding and don’t know why.  They find it unexpected given the conventional wisdom that cannabis is supposed to be a benign substance. Many initial users also get increased anxiety and, in some cases, have a panic attack that may be due to the cardiac sensations. The primary heart pounding sensation is because cannabis causes hypotension and they are experiencing reflex tachycardia. The effects may be less predictable because cannabis use can affect both sympathetic and parasympathetic pathways that can potentiate arrhythmias. A case report of cannabis induced atrial flutter (3) was described as occurring in a woman with a history of hypertension that eventually had to be terminated by an intravenous antiarrhythmic.   

Atrial fibrillation and other cardiac arrhythmias are another good reason for avoiding intoxicants including alcohol (in the supplementary analysis alcohol had a Hazard Ratio of 2.37).  It could be argued that it is basically a numbers game – since most people who use these intoxicants do not develop incident atrial fibrillation.  As of this moment, even if you have had your DNA analyzed for what are known about atrial fibrillation genes – you can’t be certain that you are not susceptible to the problem. And as outlined above there are many additional cardiac problems and that are possible from using these compounds.  The safest path is to avoid these intoxicants all together.

 

George Dawson, MD, DFAPA

 

 

References:

1:  Lin AL, Nah G, Tang JJ, Vittinghoff E, Dewland TA, Marcus GM. Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation. Eur Heart J. 2022 Oct 18:ehac558. doi: 10.1093/eurheartj/ehac558. Epub ahead of print. PMID: 36257330.

2: Marcus GM, Modrow MF, Schmid CH, Sigona K, Nah G, Yang J, Chu TC, Joyce S, Gettabecha S, Ogomori K, Yang V, Butcher X, Hills MT, McCall D, Sciarappa K, Sim I, Pletcher MJ, Olgin JE. Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation: The I-STOP-AFib Randomized Clinical Trial. JAMA Cardiol. 2022 Feb 1;7(2):167-174. doi: 10.1001/jamacardio.2021.5010. PMID: 34775507; PMCID: PMC8591553.

3: Fisher BA, Ghuran A, Vadamalai V, Antonios TF. Cardiovascular complications induced by cannabis smoking: a case report and review of the literature. Emerg Med J. 2005 Sep;22(9):679-80. doi: 10.1136/emj.2004.014969. PMID: 16113206; PMCID: PMC1726916. [full text] 

Another PSA On Pain, Opioids, and Addiction

It turns out that Twitter is an inadequate forum for discussing the issue.  Twitter is an ideal format for discovering if a poster knows anything at all about the problem.  A lot of people don't and they seem to just be there to argue.  I don't have a lot of time to waste on political approaches to medicine.  Political approaches to medicine typified by managed care companies, pharmaceutical benefit managers, and government guidelines that are supposed to improve care but don't are the reasons we have an expensive, fragmented and inefficient health care system.

The apparent political factions on Twitter consist of pain specialists who take the position that pain care and access to opioids is now being rationed and their pain patients are being unjustly treated.  They claim there is a faction of addiction specialists making various claims that they take offense to.  But my experience there is the past few days is that these are all basically red herring arguments.  A few of those claims include the idea that addiction specialists would consider pain patients "drug seekers", would recommend treating pain with only acetaminophen, are calling pain specialists "quacks", and of course that addiction specialists have some interest in distorting and overplaying the dangers of opioids.  In some cases the arguments have gotten to the absurd claim that the pain advocates (or more appropriately anti-addiction contingent) claims that most heroin users start using heroin directly rather than using legitimately prescribed or diverted pain medications first.

Where is the reality in all of this distortion?  The reality centers like most things in medicine in primary care settings.  The hundreds of thousands of internists and family physicians who provide the bulk of care for almost all problems in the US.  As I have posted on this blog many times, the evidence from both the CDC and CMS is that the majority of these physicians do a good job with opioids.  Only a fraction of their number prescribes a disproportionate amount of opioids.  Many of these physicians have a bias to underprescribing if anything.  That means the bulk of physician punitive legislation about mandatory course for opioid prescribing for these physicians will be just that - punitive toward most physicians who already know about prescribing these medications.  That legislation is also untested in terms of whether it will have any impact on the physicians who are overprescribers.

The other facet of the problem is overprescribing in general.  Part of the quality problem in medicine today is that the business and governmental management systems are focused on a brief physician-patient encounter where some medication gets prescribed.  That is the focus of the encounter. Patients expect that and come in the door with a medication request.  That results in predictable overprescriptions of medications from many classes.  The classes that reinforce their own use - opioids, stimulants, and benzodiazepines are more problematic than the rest.

At the extremes of this landscape are the pain specialists on one end and addiction specialists on the other.  Both have a broad spectrum of quality settings from state of the art to nonexistent.  These specialists know this and they know there is very little that can be done about it except to mind your own business and do the best job possible.  There are pain clinics that are "pill mills" where there is an understanding that a cash exchange with a prescriber will get you a script that can be filled on site for opioids.  That prescription is then sold in the parking lot for diversion.  There are other pain clinics where no attention is paid to addiction, psychiatric comorbidity, polypharmacy or the functional capacity of the patient being treated.  There are similarly low quality addiction treatment facilities where people are warehoused with no active treatment.  Where there is no therapeutic environment because nobody in the program is willing to consider that they may have an addiction.  There are programs where there is no medical supervised detoxification.  There are programs where there is no medication assisted treatment for opioids or alcohol use.  There are programs that do not address psychiatric comorbidity.  There are programs based on some sketchy ideas that have no proven relevance in treating addictions.  The houses of both pain and addiction specialists are not perfect because of these serious flaws.  And let's face it - the regulators of every state in the union are to blame for having so many low quality pain and addiction treatment facilities open for business and accepting reimbursement for shoddy services.   

For a moment - let's return to the idealistic world of the Twitter protagonist where the position seems to be "I am all knowing and do a perfect job."  The realities will  differ based on whether you are on the addiction or pain specialist end of the spectrum.  To illustrate, I am on the addiction end and 100% of the people are see have addictions or substance use problems.  On any given day the problematic substances average out to about 30% alcohol, 30% opioids, 20% mixed, 15% stimulants, and 5% cannabis.  Of the opioid users 30-50% have chronic pain problems.  In every case, I have a detailed discussion with the patient about how their substance use problem evolved and what keeps it going.  Over the years I see thousands of people with these problems and in that process come to know a lot about the associated issues.  My opinion is not based on my personal experience or politics.  My opinion is based on understanding the problems of thousands of people that I am supposed to help.  For example, when somebody tells me that the "average" heroin user in this country starts using heroin rather than prescription painkillers - I can say that is unequivocally wrong.  I have heard all of the details about how heroin use begins and it is almost always with a prescribed or diverted pain medication.  When somebody tells me that taking a person who is addicted to opioids and who has chronic pain off of opioids is cruel - I can also say that they are wrong.  I have had those same people tell me that they have never felt better and in less pain in years.   I can also say the following based  both on research, theory and clinical experience:

 1.  A significant portion of the population is predisposed to addiction - 

My estimate would be about 40%.  When a genetically predisposed person uses an intoxicant their reaction to it is markedly different from a person who lacks that predisposition. Opioid users report an energetic hypomanic felling where they have mental clarity like they have never experience before.  In some cases they will say that they felt like they had become the person they always thought that they could be.  This is a highly reinforcing state that leads to more opioid use.

2.  If the population predisposed to addiction is significant - the only limiting factor is access or availability -

This is the basic reality of the current opioid epidemic and of course very drug epidemic (methamphetamine, cocaine) that the US has seen over the past 200 years.  It is quite easy to look down from the high perch of a low availability area with low addiction rates to a high availability area with high addiction rates and conclude that "there is something wrong with those people".  The usual conclusion has been that they are morally defective.  This is how addiction services have been rationed, poorly researched, and fragmented over the years.  Even if you subscribe to a top health plan in the country - it is likely that you will have poor access to quality addiction care because of these attitudes.

3.  The burden of prescribing medications that reinforce their own use falls squarely on the prescriber - 

It is above all else an informed consent issue.  The patient needs to know that the medication they are taking is not a panacea and that there are significant risks up to and including addiction and death.  They also need to know that these medications can have cognitive side effects and affect their day-to-day functioning.  They should not be prescribed solely out of the notion that the physician feels like they need to do something for the patient.  There needs to be a pain diagnosis and treatment plan.  In the case of chronic pain the patient needs to know that there is no known medication that completely alleviates chronic pain and therefore continued dose escalation of opioids is not a solution.  The treatment plan needs to contain more elements than taking the opioid prescription.

An associated prescriber issue is polypharmacy.  Chronic pain is frequently associated with anxiety, depression, and insomnia.  That can lead to a contraindicated polypharmacy environment that includes a benzodiazepine, a z-drug, or a sedating antidepressant used with the opioid.  It can also lead to the patient taking alcohol or diverted sedatives on their own initiative with the opioid.

4.  Chronic pain patients taking opioids need thorough evaluations if possible -  

Some people in the Twitter debate seemed shocked by the idea that opioids are taken for reasons other than pain relief.  I suppose they would be even more shocked if they heard that there are people that take them who get no pain relief at all from them.  They taken them strictly because of the positive euphorigenic effects.  There are also people who take them despite the side effects for the same reason.  The first thing a physician needs to do is step back from the indication - prescription mode that most American physicians have been trained in to take a look at the entire prescribing landscape.

That means that is a person has come to idealize a medication or abusable substance they will start to use it for anything - insomnia, anxiety, depression, or "just to feel right to get through the day."  As many people tell me: "Look doc - if you can't get rid of this depression I know what I can take to feel OK for a couple of hours."  On Twitter and some other blogs readers are incensed that these behaviors exist and yet they are documented in the literature (see paragraph 6).

When I say if possible I am more aware of the fact that patients lie to physicians than non-addiction specialists.  I have had an endless number of patients tell me that they can get whatever addictive medication they want out of one physician or another.  The Mayo clinic had an addiction medicine conference three years ago and one of the presenters was a patient in recovery who basically talked about how he systematically lied to physicians to get opioids for years.  He talked about how he could identify a physician who would give him the script that he wanted and who would not.  In the case of the latter he would just move on to another clinic.

Many non-addiction specialists consider it to be poor form to suggest that patients lie.  That denies the basic reality that everybody lies.  It also denies the reality of addiction, that you are transformed into a person who is dishonest and a person that you never thought that you would become.  In the addiction field it is critical to acknowledge this to help people deal with guilt and shame so that they can recover.  The worst thing that can happen is to collude with dishonesty when the final result is the prescription of an addictive drug.  I do not consider it to be an issue that I can get this history when the physicians being approached for the medication cannot. It is all part of the illness of addiction.  On the other hand, if you are the opioid prescribing physician - the amount of information that you can get asking the direct questions about problematic use is not known until you try it.   

All things considered it is possible to treat people with chronic non-cancer pain with opioids.  I have been involved in that treatment before I switched to seeing only patients with addictions.  I consulted with some of the top pain experts in the state.  All the limits in this post need to be acknowledged and cautiously addressed.  The treatment of chronic pain is not perfect, I know that because I see a lot of the failures.  Addiction treatment is not perfect either.  The treatment needs to be highly individualized.

I wish that I could provide more clear guidance to the patients involved.  As an individual I cannot just start pointing fingers at the places (pain clinics and addiction treatment) that I think should be shut down.  I think that you need to depend a lot on your primary care physician referring you to places that he or she knows will do good work.  On either the addiction or pain end of the spectrum - there has to be more going on than the prescription of medications.

Even the most basic psychological models suggest that other cognitive, emotional, affiliative, spiritual and reconditioning changes need to occur.


George Dawson, MD, DFAPA 

  








   

OIG Approach To Medicare Part D Opioid Prescribing

The pharmacoepidemiology of opioids in the United States depends on a fragmented approach.  I recently posted a CDC study that used a commercial pharmacy database to look at the characteristics of opioid prescribing across individual counties in the United States.  In the past week I came across this data brief from the Office of Inspector General (OIG) of the US Department of Health & Human Services.  Their database is the 43.6 million beneficiaries of Medicare Part D.  Their stated goals are to protect beneficiaries and the community from prescription drug abuse, to prevent diversion and illegal sales, and to protect the program from fraud and unnecessary expense.

Their methodology is unique.  They look at prescription drug events (PDE) for all opioids prescribed in 2016 that are paid for by Medicare Part D.  Any prescription paid by cash or by another insurer is not counted.  Every time a prescription is dispensed and covered by the program a PDE record is sent to CMS (Centers for Medicare and Medicaid Services).  In this case they calculated total spending on opioids, total Schedule II and III opioid prescriptions, and a number of parameters that look at total cost.  They also determined the the prescriptions per beneficiary, and the average daily morphine equivalent dose (MED).  In most of the literature on opioid dosing the milligram morphine equivalents (MME) is a common measure.  MME is just the total mg of opioid multiplied by a conversion factor.  The MED is basically the same measure but it factors in the total duration of the prescription.  As an example for a one day supply of either Vicodin (hydrocodone) 10 mg tabs or Percocet (oxycodone) 5 mg tabs:

 hydrocodone:  12 tabs x 10 mg = 120 mg x 1 (conversion factor) = 120 MME or MED

oxycodone:      16 tabs x   5 mg  = 80 mg x 1.5 (conversion factor) = 120 MME or MED

In addiction practice these are common doses encountered in the low range of prescription opioid use disorders.  I used the brand names for hydrocodone and oxycodone preparations here because that is what people commonly report to me and it typically requires more investigation.  For example "Percocet" or "Perc30s" commonly refers to higher dose oxycodone without acetaminophen - a single 30 mg tablet of oxycodone or 45 MME.  The authors of this brief do not need to be concerned about those data discrepancies because they are able to get specific claims data.

In terms of outcome data, they looked at all of the prescriptions and cost variables as well.  They looked at total exposure.  One in three Medicare Part D beneficiaries received at least one opioid prescription.  That amounts to 14.4 million people out of a 2016 beneficiary base of 43.6 million people.   There were a total of 28.2 million hydrocodone-acetaminophen prescriptions, 5 million oxycodone-acetaminophen prescriptions and 14.8 million tramadol prescriptions.  Tramadol is not typically included in opioid studies even though the M1 metabolite is a mu receptor agonist.  Tramadol is a prodrug metabolized by CYP2D6, metbolism is necessary to to create M1 and slow metabolizer are less likely to experience the analgesic effect and addiction risk.

Of these beneficiaries 501,008 received high dose opioids (MED > 120 mg/day).  The indication here was for noncancer or chronic noncancer pain.  Hospice patients and cancer patients were excluded.  The most common opioid prescribed in this high dose group was oxycodone 30 mg.  The study also defined extreme amounts of opioids as an MED of 240 mg and 69,563 patients received that amount.  There were 678 patients receiving high extreme amounts a MED of 1,000 mg for an entire year.  The concern with very high levels is whether the prescriptions are indicated and whether they might be diverted.  The authors also suggested that fraud could be an issue due to stolen Medicare identification number.  They did give an example of a patient who got 62 opioid prescriptions on one year (61 from the same family physician) with an average daily MED of 3,130 mg.

The brief also estimates the degree of doctor shopping or seeking prescriptions from more than one physician and pharmacy.  The criteria used for this report was 4 prescribers and 4 pharmacies.  A total of 22,308 beneficiaries met that criteria and they also had an average daily MED > 120 mg for a period of three months.  They also identified 162 beneficiaries who got opioid prescriptions from 10 different prescribers and 10 different prescribers in the same time period.  Even larger number of prescribers and pharmacies were noted in the most extreme cases.  That number represents about 0.02% of the total number of beneficiaries using opioids and that is the same order of magnitude of a previous estimate from a large commercial prescription database (4).  

Using the estimates of high dose opioids and degree of doctor shopping allowed for an estimate of serious risk of opioid overuse or overdose.  The number estimate in that category was 89,843 or about 0.6% of the entire group taking opioids.

The brief also looks at the issue of who is prescribing the opioids.  For the 89,843 there were an estimated 115,851 prescribers who wrote at least one of those prescriptions.  A total of 401 prescribers were determined to be "far outside the norm".  One hundred and ninety eight ordered opioids for patients getting extreme amounts of opioids (MED of 240 mg), 264 ordered opioids for patients who appeared to be doctor shopping, and 61 ordered opioids for patients who were members of both groups.  The total number of prescriptions written by prescribers in this group was 256,260 opioid prescriptions.  There were 15 prescribers who ordered opioids for > 98 beneficiaries receiving extreme amounts (MED of 240 mg).   Of the 401 prescribers with questionable prescribing 1/3 or 133 were nurse practitioners (N=81) or physicians assistants (N=52).

Are there any conclusions possible from this administrative look at opioid prescribing in a subset of Medicare patients?  I think that there are a few.  My conclusions assume that generalizations from this data are possible:    

1.  Opioids are commonly prescribed to Medicare recipients - and the vast number of these prescriptions appear to be appropriately managed.

2.  A small number of prescribers appear to be responsible for most of the inappropriate prescriptions - and there are some outliers practicing at the extremes in terms of prescribing patterns.  Very extreme prescribing described in a few cases would appear to be a function of unnecessary use rather than patients with special needs who require extremely high doses of opioids (MED > 375 mg).  That is an important point because concentrations of high dose opioid prescribing is often attributed to the special needs of patients or referral patterns resulting in concentrations of these patients and the need for the prescriber to write prescriptions for these amounts.  If this was a case of biological variability - a much larger fraction of the patients who require extreme amounts of opioids.

3.  The problem of inappropriate prescriber appears to be easy to follow on the CMS data base - the standard political approach to the opioid epidemic is to blame all doctors and mandate various education programs about opioid prescribing.  It should be clear that a minority of physicians or in this case prescribers are problem and there should be a targeted approach.  At the very minimum the prescribers in the top 1% of all prescribers or the group who is prescribing extreme amounts of opioids, to people who are probably doctor shopping, or both should be receiving active feedback from CMS.

4.  Not counting opioids prescribed for cancer or hospice care is an important omission -  This is a problem with very little research or policy making.  Patients undergoing end-of-life care are  prescribed liberal amounts of opioids for pain relief.  There is no question that these patients should have adequate pain relief by whatever medication is necessary.  The question is what happens when there are opioids from these prescriptions that the patient never uses?  One palliative care study (3) noted that of the hospice care agencies responding to their poll, over a third noted that substance use and diversion were a problem for their agency.  Diversion of drugs is known to occur in health care systems where there is monitoring and checks and balances.  There are large amounts of opioids out in in-home hospice care settings with much less accountability.  A similar study looking at the amounts of opioids prescribed in these settings and what happens to that medication is needed.

5.  Opioids are not prescribed in isolation - CMS and the OIG are not medical research organizations.  A more comprehensive approach to the problem would look at all of the medications that these patients are receiving and not opioids in isolation.  Benzodiazepines frequently accompany opioid prescriptions and in some cases with sedative hypnotics for sleep.  Prescribing both compounds can lead to serious and in some cases fatal drug interactions.  That would result in an additional category of inappropriate prescribing of opioids.

Although this is an administrative database, it does illustrate how this data can be used for pharmacosurveillance purposes.  There was emphasis about the cost of opioid prescribing and the need to prevent fraud from a CMS perspective.  The data could also be used to provide valuable feedback to physicians and other prescribers as well as politicians and regulators.

It can be used to counter some myths that seem to exist on both sides.


George Dawson, MD, DFAPA




References:



1:  US Department of Health and Human Services: Office of the Inspector General.  Opioids in Medicare Part D: Concerns about Extreme Use and Questionable Prescribing.  HHS OIG Data Brief OEI-02-17-00250.

2: CDC, “Increases in Drug and Opioid-Involved Overdose Deaths: United States, 2010–2015.” MMWR Morb Mortal Wkly Rep, December 30, 2016, pp. 1445–52. Accessed at https://www.cdc.gov/mmwr/volumes/65/wr/mm655051e1.htm on July 16, 2017

3: Blackhall LJ, Alfson ED, Barclay JS. Screening for substance abuse and diversion in Virginia hospices. J Palliat Med. 2013 Mar;16(3):237-42. doi: 10.1089/jpm.2012.0263. Epub 2013 Jan 5. PubMed PMID: 23289944

4: McDonald DC, Carlson KE. Estimating the prevalence of opioid diversion by"doctor shoppers" in the United States. PLoS One. 2013 Jul 17;8(7):e69241. doi: 10.1371/journal.pone.0069241. Print 2013. PubMed PMID: 23874923.

LinkedIn Headline Throws Psychiatrists Under the Bus

There is was - plain as day on my LinkedIn feed:  "Psychiatric drugs killing more users than heroin, cocaine, say health experts".  Seems like a headline more fitting for one of the large antipsychiatry web sites out there.

What?  Addictive drugs and the current overdose situation is something that I know more than a little about.  I lecture about it.  I treat the addicted.  I was in the medical school pharmacology classes where they taught us it is practically impossible to kill yourself with benzodiazepines unless you mix them with alcohol.  Of course today we know that it is very easy to kill yourself by mixing benzodiazepines with opioids.

My first problem was the characterization that benzodiazepines are psychiatric drugs when 80% of the prescriptions are from non-psychiatrists (1).  This is a common tactic used to impugn monolithic psychiatry.  Some authors try to link the ills of all antidepressant, antipsychotic, and mood stabilizing medication to psychiatrists.  The only medication that psychiatrists prescribe more of than primary care physicians is lithium.  Most primary care physicians consider lithium to be a weird little niche drug that they would prefer psychiatrists handle.  For a while psychiatrists were also reluctant and prescribed a number of less effective medications.  Part of that was based on hype, but I am sure there was at least a partial unconscious motivation that the burden of lithium prescribing could be avoided.

The secondary argument of course is that psychiatrists are thought leaders in this area and convince the poor unthinking primary care physicians to prescribe benzodiazepines and add them to opioids!  There are no Key Opinion Leaders (KOLS) advocating for the widespread use of benzodiazepines. Instead I am asked to write about reasons to avoid prescribing them.  Since the entire class has been generic for some time there is no pharmaceutical marketing.  No - you really don't have a leg to stand on if you are making that argument.  Although antipsychiatrists don't generally have a leg to stand on - let's assume there is at least one person who is interested in the facts rather than hum-drum antipsychiatry fake news.

It turns out there is actual data out there.  Thoughtful analyses from both NIDA and the CDC that look at the issue of overdoses on various forms of opioids and cocaine, but also the various combinations of opioids plus either cocaine or benzodiazepines.  All of the data I am posting here is available at this link.  It is all public domain from employees of the US Government and they have done an excellent job with the details of the current drug epidemic.

       
The  first two slides are total death from all opioid overdoses and heroin overdoses.  Looking at 2015 those numbers are 33.091 and 12,989 respectively.  The next slide looks at total cocaine deaths.  And in 2015 that number was 6,784.

The final slide looks at benzodiazepines on their own (1,306) and benzodiazepines plus opioids (7,485).  Note that concomitant benzodiazepine use with opioids is a major risk factor for death from that combination.  The annual benzodiazepine deaths have remained relatively constant until the onset of the opioid epidemic.  It is well known that some opioid users take benzodiazepines to enhance the effects of opioids.  

To recap, if the heroin deaths in 2015 were 12,989, the cocaine deaths were 6,784 and the benzodiazepine deaths were 1,306 the headline is glaringly inaccurate.  The only way that benzodiazepines are as lethal is if they are mixed with opioids - a fairly common occurrence.  That is not a combination prescribed by psychiatrists.  The overwhelming number of deaths due to drug overdose are from opioids - 33,091/year.

These combinations have been studied in persons on maintenance opioids (methadone and buprenorphine) who are also prescribed benzodiazepines, sedative hypnotics and in a recent study (4) - pregabalin.  The authors of that study found that of their sample of 4501 patients - 32.8% were prescribed benzodiazepines, 40.8% z-drugs (zolpidem,  zopiclone, eszopiclone, and zaleplon) and 22.2% were prescribed pregabalin.  In their study, the pregabalin and z-drug prescriptions were associated with more overdose deaths and the benzodiazepines were associated with more overall deaths.

That combination accounts for the common experience of opioid and heroin overdose deaths in small towns across America.  Those overdose deaths in small town American were unheard of before the current epidemic.

It doesn't hurt to get the facts straight when attempting to throw psychiatrists under the bus, even though in the majority of cases - facts are the last thing any of the critics seem to consider.



George Dawson, MD, DFAPA



References:

1:  Cascade E, Kalali AH. Use of Benzodiazepines in the Treatment of Anxiety. Psychiatry (Edgmont). 2008; 5(9): 21-22. Link

2: Olfson M, King M, Schoenbaum M. Benzodiazepine Use in the United States. JAMA Psychiatry. 2015;72(2):136-142. doi:10.1001/jamapsychiatry.2014.1763

3: Kjosavik SR, Ruths S, Hunskaar S. Psychotropic drug use in the Norwegian general population in 2005: data from the Norwegian Prescription Database. Pharmacoepidemiol Drug Saf. 2009 Jul;18(7):572-8. doi: 10.1002/pds.1756. PubMed PMID: 19402032.

4: Abrahamsson T, Berge J, Öjehagen A, Håkansson A. Benzodiazepine, z-drug andpregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug Alcohol Depend. 2017 May 1;174:58-64. doi: 10.1016/j.drugalcdep.2017.01.013. Epub 2017 Feb 28. PubMed PMID: 28315808.

Attribution:

All slides from NIH/NIDA and are assumed to be public domain.

Enhancing The Volkow-Collins Approach To The Opioid Epidemic

Nora Volkow, MD - Director of the National Institute on Drug Abuse and Francis S. Collins, MD, PhD - Director of the National Institutes of Health co-authored a paper on the role of science in the current opioid crisis.  Full text of the article is available free online from the New England Journal of Medicine at the reference given below.  In the article the authors review the scientific interventions at three levels of care in treating opioid addiction and use, treating and preventing overdoses, and the treatment of chronic pain.  The treatment of chronic non-cancer pain (CNCP) with opioids can be realistically viewed as the precipitant of this epidemic.  The brief 4 page review is a good rapid review of the science behind these interventions.  The level of cooperation between NIDA and NIH with private industry may surprise a few people but as the authors point out -  the level of mortality with the current epidemic needs to be approached with urgency at all levels.

At the level of opioid overdose prevention and reversal - more potent and long lasting opioid antagonists are being developed to counter exposure to fentanyl and carfentanil appearing at an increasing rate on the street.  Narcan Nasal Spray is probably the most effective and practical outcome of the industry-NIDA partnership.  A wearable device that can detect signals of an impending overdose and administer a μ-opioid receptor antagonist is mentioned.  At the level of addiction treatment methadone, buprenorphine, and extended-release naltrexone are all mentioned as current treatments for opioid use disorder.  Access to providers is discussed as a limiting factor.  vaccines and novel receptor approaches are discussed as potentially new pharmacological approaches to the problem.  New approaches to chronic pain are discussed in greater detail.  Cooperation between the NIH and industry is emphasized again in terms of getting these approaches to market and clinical use.  In the concluding section - the emphasis on NIH-industry partnerships is a central theme.  The argument makes imminent sense, but after two decades of rancorous debate about the effects of pharmaceutical company pizza on prescribing - this level of access to the highest level of taxpayer funded research is somewhat stunning.

But what else might be immediately useful?  I can concentrate just on buprenorphine and come up with a couple.  Anyone working with this compound and people who are addicted to opioids routinely encounters problems with its use.  It is common to treat people who still have withdrawal symptoms and cravings on the  recommended doses and remain at high risk for relapse even after being treated with what is described as one of the best current therapies.  Taking a look at the recommended dose range from the package insert:

The upper limit of the recommended dose is 24mg/6mg buprenorphine/naloxone per day for SUBOXONE. The reported lack of significant increase in brain mu‐receptor occupancy between doses of 16 mg and 32 mg implies that there should be little difference in clinical effectiveness at doses between 16 mg and 24 mg in most patients. When a patient expresses a need for a higher dose, consider the possible causes (e.g., environmental stressors or psychosocial issues that increase cravings or possible drug interactions). Before increasing the patient’s dose, explore other alternatives. Also consider the possibility that the patient may be exaggerating symptoms to obtain additional medication for diversion. (p 34-35).

And:

The recommended target dose is 16 mg buprenorphine/4 mg naloxone per day. Clinical studies have shown that this is a clinically effective dose. Although lower doses may be effective in some patients, for most patients, a 16 mg dose should alleviate withdrawal symptoms and block or attenuate the effects of other opioid agonists for at least 24 hours. (p. 34)

In clinical practice there is a wide range of effects to buprenorphine doses.  The FDA approved considerations show the subjectivity involved in adjusting the dose.  But that is even an understatement.  There needs to be a much greater investigation of the causes of continued craving and withdrawal symptoms when the patient is taking a recommended dose of buprenorphine.  This may be a genetically determined phenomenon either at the pharmacokinetic or pharmacodynamic level.  That is only partially accounted for by drug interactions.

Investigation of withdrawal symptoms and continued craving is more than just a passing concern.  It potentially determines who will be able to remain on maintenance therapy and stay off of heroin.  It is important because a significant number of these patients are being actively treated for psychiatric disorders with antidepressants, anxiolytics, atypical  antipsychotics and mood stabilizers.  How much of that medication use is due to inadequate treatment with buprenorphine and the common symptoms of insomnia, anxiety, and depression associated with opioid withdrawal.  These are all very complex clinical situations.  Many of these patients have a life long history of stress intolerance and there can be a reluctance on the part of clinicians especially if they have no mental health training to explore and treat those problems.  Once the patient has been indoctrinated into the idea that a maintenance medication is going to help them stay off heroin - it is a difficult transition to now say that all of these other factors are now important and need to be addressed.  That is especially true when some of the existing buprenorphine studies minimize counseling or are publicly presented as "counseling adds nothing to the results obtained with buprenorphine."  Finally, there is a large social media movement of people who want to stop buprenorphine and are warning others about it.  What is behind this widespread dissatisfaction and what needs to be done to resolve it?  The overall impression that all of the issues in this paragraph leaves is that buprenorphine is another heavily hyped medication that does not live up to the claims.  All of these areas could use much clearer input from NIDA through additional scientific investigation.

Additional studies on drug interactions with buprenorphine are critically needed.  I use a standard commercially available drug interaction software package.  Any time I enter a psychiatric medication I get a warning to consider to modify therapy and a list of 230 potential drug-drug pharmacodynamic interactions at the CNS level.  Since there is a high prevalence of patients on maintenance psychiatric medications this represents a deterrent to some physicians, especially if they are not psychiatrists and they are in a state with an unfavorable malpractice environment.

The next issue is determining who is susceptible to opioid overuse and dependence.  In my mind the phenotype is very clear.  The person who takes the first opioid tells me that they either "fall in love with it" or they experienced an intense euphoric and almost hypomanic effect.  They felt transformed by the medication into a person that they had always wanted to be.  Side effects are modestly effective deterrents, but I have been told that side effects and a complete lack of analgesia are acceptable in order to get the intense, euphoric high.  How can these people be identified?  The authors discuss biomarkers for pain and pain relief - but the single-most important biomarker would identify this high risk group of patients for addiction.  There are currently commercial databases out there that poll their members on various traits and symptoms.  Can NIH or NIDA design the polling questions and look for markers in these existing databases?

Even before that marker is identified, is there a simple strategy that could be used in clinical practice? Could a clinician tell a patient to self monitor for the intense euphoria and report back to the physician as soon as possible if it occurs?  Could the patient be told to just dispose of the pills by bringing them in to the pharmacy if euphoria and thoughts of dose escalation occur?

These are some thoughts that come to mind that might be immediately useful.  They would address both the limitations of medication assisted treatment and identifying the at-risk population for primary prevention of opioid use problems.                
    

     
George Dawson, MD, DFAPA

1: Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017 May 31. doi: 10.1056/NEJMsr1706626. [Epub ahead of print] PubMed PMID: 28564549.

Lawyers, Libertarians, and Journalists On the Opioid Epidemic

It was a perfect confluence of events today.  At one point or another I heard or read about somebody's theory of why there was an opioid epidemic, deaths from drug use, and who was to blame.  Although some of the discussants were quite heated they all had one thing in common - they were all dead wrong.

Let me start with the lead story - the Attorney General of the State of Ohio suing drug manufacturers for the massive opioid problem in that state.  I say massive because there are an estimated 200,000 opioid users in the state and an associated mortality.  If you listen to the story (1) many local coroners and morgues are overwhelmed by the body count.  I heard the story on Minnesota Public Radio on the drive home tonight.  Ohio Attorney General Mike DeWine is suing Purdue Pharma, Johnson & Johnson, Teva Pharmaceuticals, Endo Health Solutions and Allergan for their role in the opioid epidemic.  Apparently the state of Mississippi filed the first law suit in the area.  The AG alleges that these companies basically convinced physicians through their questionable marketing efforts that these drugs were much safer than they really were and more effective for the conditions that they were supposed to treat.  Robert Siegel the reporter made an attempt to blame physicians instead and asked why they were not named in the law suit.  The AG's position was that the culture of medicine was affected by the false promotion and that it will take a while to change things around.  See the press release here for the exact position of the AG.  A copy of the entire complaint by the AG is available here.

The second story (2) came to my attention on my Facebook feed.  This was a case of  Ross Ulbricht - who was apparently convicted and sentenced to life in prison based on operating a darknet market that he created called Silk Road.  The conviction was apparently for money laundering, conspiracy to traffic narcotics, and computer hacking.  My interest in this case has nothing to do with the charges, the defendant himself, the conviction or the sentencing but the reaction on various web sites about the case.  There is a consensus on some of these web sites that he was offering valuable service for adults who want to come together and freely exchange items that it might be difficult for them to exchange in other places.  The associated arguments are that competent mature adults should be able to do this, that any interest the state has in suppressing such activity is an inappropriate intrusion on individual rights, and that in fact a service like this was essentially competing against cartels and may put them out of business. Some suggested that there was a conspiracy between the state and cartels to put sites like this out of business.  

All of these arguments fall flat to an addiction psychiatrist like me.  They seriously underestimate the effect that an addiction has on the brain and conscious state of an addicted individual.  Imagine what it is like to get out of bed in the morning and the very first conscious thought is: "How can I score some dope today so that I can function?" At that stage you are no longer a competent adult able to weigh decisions and make them in your best interest.  All of your decisions are weighted in the direction of ongoing drug use and addiction.  That is true if you are on the darknet looking for drugs or standing on a street corner in Ohio.  That is true if you are sitting in a physician's office and telling them what you think they need to hear to enable them to prescribe you more opioids.

The second aspect of opioid addiction that is difficult to understand is the genetic predisposition to addiction.  There are still a lot of pop psychology theories about addiction being just a bad habit or a lack of moral character that seem to explain the differences between people with addiction and people without addictions.  The fact is a substantial part of the population is genetically vulnerable to addiction and it is just a matter of whether or not they are exposed to a highly addictive drug.  If I had to estimate, my best guess would be that number is at least 40% of the population.  By that I mean that 40% of the population will get an extremely euphorigenic response to opioids (whether or not they work for pain).  They will remember that response and if exposed to more opioids are much more likely to use them than not use them.

That is what makes it so hard to stop this epidemic.  Without those two basic features of addiction there is no unlimited demand for addictive medications from pharmaceutical companies.  There is no need to go to a part of town that a person would never typically travel in to purchase diverted prescription opioids or heroin.  There is no need to search out opioids or other addictive drugs on the Internet or the dark net.

Doctors don't get off the hook.  All physicians are taught about controlled substances and the schedule of controlled substances.  All physicians know that opioids are scheduled according to their addictive potential.  The problem is that most physicians do not know how to interact with people who have significant addictions, and even experts can be fooled.  Most physicians have an incredibly naive approach to addiction and how they can prevent it or approach it once it is established. The cultural norm that physicians help people by prescribing them medications, combined with the fact that physicians are trained to help people, creates a powerful force to continue to prescribe addictive pain medications.  The absence of competent detox facilities is another.  

Pharmaceutical companies, doctors, judges and prosecutors - the pro and anti-blame rhetoric around this issue is intense and unrelenting.   It is not any easier to stop the current opioid epidemic when lawyers, libertarians, and reporters are spreading the blame around to anyone or anything other than the real cause of the problem - the addiction itself.

Start there - treat it as a public health problem and start to make progress.


George Dawson, MD, DFAPA      


References:

1:  Ohio Sues Drug Companies Over Role In Creating Opioid Epidemic.  All Things Considered; may 31, 2017.  Transcript and audio clip.

2:  Brian Doherty.  Ross Ulbricht Loses His Appeal Over Conviction and Sentencing in Silk Road Case.  Hit and Run Blog.  Reason.com  May 31, 2017.


Supplementary:

A reminder about the Ross Ulbricht case.  I am not focused on the case per se or the War on Drugs.  I am solely focused on the argument that anything can be openly traded on a market between consenting adults.  I do not dispute the argument that the sentence was excessive or any other arguments for that matter.

KFF / Washington Post Survey Of Opioid Users

The Kaiser Family Foundation and the Washington Post have released a survey of prescription opioid users to the general public.  Reading through this survey and the accompanying explanations does not seem to match a few realities about the ongoing opioid epidemic.   Some important dimensions of addictive drugs are left out.  It is not  clear to me who designed the survey.  My only intent here is to critique it from the standpoint of an addiction psychiatrist and the current literature on what may have been more comprehensive questions.  The key dimension with opioids and any other potentially addictive drug is that a drug is being prescribed and a certain part of the population will over administer as a result of their biology.   The exact percentage of people with that tendency is unknown.  After reading through the survey results, this survey suggests the number of people is about a 30% - but there are some red flags.  Other literature suggests that the number is lower. The current opioid epidemic correlates with wider availability of these medications.

In order to understand the right questions to ask in a survey to detect problems with opioid use a brief review of the reinforcing effects of opioids are in order.  On the positive reinforcing side many people feel and intense euphoria with first use.  Many report increased energy and a sense of well being. In some cases people feel that they are thinking more clearly and in the extreme that their personality has been transformed.  Many people report that they feel like they have been transformed into the person they thought that they could always be.  All of these perceptions of the effect of opioids are highly reinforcing of future use.  It also highlights the problem when opioids are given for minor injuries in that a susceptible population is being exposed to these effects.  Another area of concern is post operative use.  A significant number of people continue to take opioids long after surgical procedures are done and wound healing is accomplished.

Another source of positive reinforcement is what has been considered self medication.  When a medication has the properties noted in the previous paragraph, it can take on magical qualities.  In American culture illicit drugs and opioids in particular take on magical qualities.  They are seen as the silver bullet for acute and chronic pain - when neither case is true.  When that belief is widespread  and the medication reinforces its own use - people begin to use it for insomnia, anxiety, depression, and as a general solution to stress. Some people will report that they just "don't want to feel anything" and will take enough of the drug to do that.  Taking the medication for these secondary effects can also reinforce use and lead to escalation of the dose.

Negative reinforcement is another aspect of addictive drugs.  In the case of negative reinforcement, the frequency of any behavior to decrease the response to an aversive stimulus increases.  With opioids the aversive stimulus is opioid withdrawal and the early symptoms are associated with cravings to use opioids and continue the addiction.  During that phase of addiction there is typically a tolerance to the euphorigenic and other positive reinforcing effects of opioids.  People are using opioids at this time primarily to prevent withdrawal but now the withdrawal has a host of associated effects like insomnia. anxiety, and depression that also must be avoided.  

That landscape of addiction, tolerance, withdrawal, positive reinforcement and negative reinforcement does not make this an easy problem to study.  There is an even larger problem and that is that decision-making is compromised in the direction of continuing the addiction.  That translates to dishonesty about use and in many cases dishonest behavior necessary to acquire and use drugs.  That dishonesty in the service of addiction is a major problem in studying addiction and providing clinical services.  It is the reason for toxicological testing, collateral information, and establishing sober environments with no access to intoxicants.  Any survey of patients with potential addictions should address how this issue has been handled in the sample.  Studies have been done on the predictive value of specific behaviors with opioids like purposeful oversedation, lost prescriptions, mixing alcohol with opioids, early prescription renewals, etc. but many of these stuides also depend on self report.

How does the KFF/Washington Post survey do?  First off the random sample is a combination of people using prescription opioids (N=807) or in the household where a person uses opioids (N=187).  The indication for opioid use is chronic noncancer pain.  The threshold was using for two months in the past 2 years.    Only 55% of the respondents were currently taking opioids.  The study was all done by telephone interview.  The respondents ranked prescription painkiller abuse as a serious problem (84%) and only slightly less serious than obesity, cancer, heart disease, alcohol abuse or heroin abuse (89-95%).  The lowest ranking of seriousness in that category was heroin abuse at 89%.  25% of the respondents began taking opioids for postoperative pain and 44% for chronic pain.

The section on motivation for using opioids indicated that pain relief was the major reason people were taking opioids and 92% or people ranked pain relief as either "very well or somewhat well".  Secondary reasons included dealing with stress, to get high, or to relieve tension (12-34%).  Of the secondary reasons getting high has the highest ranking of 34%.  There are several chronic pain studies that suggest that for chronic neuropathic pain - the relief from opioids is on par with pain relief from non-opioid medications for the same application.

Physicians did not get rated very highly in the survey with only 2/3 of them warning patients about the addictive potential of opioids or talking about non-opioid strategies for treating pain.  Only 1/3 of physicians had a plan to get people off opioids.  Physicians did better in terms of warning patients not to use alcohol concurrently with opioids and discussing side effects but only slightly better in terms of advising patients on keeping opioids out of the hands of others.

In medical practice, especially with electronic health record systems there is often an emphasis on pre-existing alcohol or substance use disorders.  The closest this survey comes is to ask about the number of alcohol drinks per week.  About 22% of respondents had more than one drink per day.  There is a lot of room on the high side.  There is also a dissociation between known addictive disorders and opioid prescriptions.  Many physicians believe that people with a known addictive disorder to a non-opioid including alcohol can control their use of opioids for pain.  They are often reassured by these patients who tell them that they have never had a problem with opioids.  

Only 18% of respondents had difficulty getting their prescriptions refilled.  That contrasts with the 1/3  of patients taking the medication to get high.

The degree of polypharmacy in the sample was striking with 32% taking 7 or more prescription drugs and 25% taking 4-6 prescription drugs.  Slightly over half of the sample were taking medications for insomnia, depression or anxiety.  Benzodiazepines and z-drugs were not specified.  The survey did ask about alcohol use while taking opioids and it is a clear problem.  In addition practice it is common to see patients who are using benzodiazepines and z-drugs with opioids.   It is also common to see people taking one, both and both in combination with alcohol.  In addiction practice it is important to determine if anxiety, depression, and insomnia are primary, caused by the addiction, or associated with chronic intoxication or withdrawal states.

On the specific question of risk of addiction 2/3 of respondents said that "The benefits of pain relief outweigh the risk of addiction."  One third of the sample said they were dependent on the drugs and would find them hard to stop.  When that question was rephrased with the description "addicted" 23% thought they were addicted to the painkillers.  Of the respondents who thought they were dependent or addicted - 1/3 sought treatment and 2/3 did not.  An interesting study might look at videotapes of the informed consent procedure and what information the patient recalls  after that procedure.  My experience suggests that a large percentage of people who are actively using opioids and alcohol do not recall what was said in the initial consultation by comparison with the documentation.

The survey attempts to parse blame  for the prescription painkiller epidemic and in that series of questions the groups ranging from most to least blame (61% to 15%) were ranked the patients themselves > doctors > drug companies > government > hospitals > law enforcement > pharmacies and pharmacists.  The key elements here are wider access to opioid medications as a result of an initiative to treat chronic pain and a movement away from gatekeepers.  

Given the limitations of a survey, I thought that the self assessment of the number of people who though they were dependent or addicted to painkillers was striking.  The number  of people seeking treatment though low is much higher than what has been estimated using other methodologies like the NSDUH survey.  It may suggest that survey technologies alone or in combination with other corroborative methods may be useful in further studies of this phenomenon.  One of the real questions out there is the number of people in the wild who are at high risk for the initial highly reinforcing properties of opioids.  If I had to guess, I would put that number at about 40% of the population.  There is a significant and slightly smaller group who get immediate negative effects and do not tolerate opioids at  all.  By definition, there may be a safe third portion of the population who can benefit from opioids with very low addiction risk.  Clearly defining that population, hopefully with biological markers would have a significant impact on the problem of addiction to opioids.  It would also have implications for a more elaborate diagram of the neurobiology of opioid addiction.

For physicians the problem is as clear as ever.  The vast majority of this sample (95%) got prescription pain relievers to alleviate their acute or chronic pain and 1/3 end up using the drug for other reasons including getting high.  That is due to the inherent properties of addictive compounds.  The practical problem is how to address that risk in medical practice.        

    
George Dawson, MD, DFAPA

References:

1:  Drew Altman.  Understanding Who Opioid Users Are Underscores Challenges.  December 19, 2016.  KFF.org

2:  The Washington Post/Kaiser Survey: 1 in 3 Long-Term Prescription Painkiller Users Think They’re Addicted or Dependent.  KFF.org

The Reality Of Burprenorphine Therapy

It is increasingly popular for politicians and healthcare businesses to discuss their ideas about how to end the opioid epidemic that they started.  One of the common themes is widespread availability of both buprenorphine maintenance therapy and naloxone opioid antagonist therapy for acute overdoses.  I am certainly not opposed to either and in fact work in an addiction treatment environment where these are two of several medication assisted therapies used to treat addictive disorders.  I am skeptical of the idea that broad prescribing of these therapies in either primary care clinics or some treatment settings will ever occur.  Naloxone will be more readily available because there is a movement to create easy access without a prescription.  That will never happen with buprenorphine.  Last week - an article in JAMA backs up my skepticism (1).

The JAMA article looks at 3234 buprenorphine prescribers in the 7 states with the most buprenorphine prescribers.  In their introduction the authors talk about the policy initiatives to increase the maximum patients per prescriber from 30 to 100 patients after a year.  The average monthly patient census per month varied from 7 - 22 patients and a median monthly patient census of 13 patients.  The duration of treatment episode was 53 days.  This illustrates that the monthly census was well below the allowed limits and the duration of treatment was well below the recommended maintenance guideline of 12 months.  They cite evidence that novice prescribers wanted more access to substance use counselors or other prescribers with more experience as potential limiting factors.

The authors of this article do not offer other explanations for the low rate of buprenorphine prescribing.  I have a few.  I really do not like stigma arguments.  To me stigma seems like an excuse for not being able to overcome societal biases toward a particular problem.  I don't see how you can train to be a physician and not have most of these biases wrung out of you.  With addictions and mental illnesses there may be a stronger bias based on personal experience.  Some physicians may have come from a family where the the father was an alcoholic or a heroin addict living homeless on the street and everybody was used to that idea.  Some physicians may have come from families where the father was still drinking and dying of cirrhosis and the familiy opinion was that he "has a right to drink himself to death" rather than get treatment that he did not want in order to stop drinking.  Other physicians may have come from families where father and his father both had severe alcoholism.  Grandfather drank himself to death by the time he was 50.  Father got treatment for his alcohol problem and was in stable recovery for years.  All of these personal experiences and the reactions to them will affect how a physician approaches alcoholism and addiction.

Those biases are all part the the inevitable decision-making process that leads physicians down specific career paths.  I have lost count of the number of times that another specialist told me that they really liked psychiatry and were considering the residency except for certain features of the field.  A couple of examples include needing to try to predict suicide and aggression and live with the consequences or dealing with a certain diagnostic group like patients with severe personality disorders.  People are less specific about addictions, probably because as medical students and interns we all see the severe effects.  Most of the acute care hospitals where physicians train have 30-50% of their admissions based on the acute effects of alcohol or drug use.  That includes many admissions for acute hepatitis, hepatic encephalopathy from cirrhosis, acute alcohol poisoning, acute overdoses on addictive drugs, and various psychiatric morbidities like delirium and psychosis from the acute effects of addictive drugs.  It is less obvious but addictive drugs and alcohol are also overrepresented as reasons for admission to surgical trauma units and burn units.  Most interns and residents see these effects first hand and develop both short term and long term perspectives on these problems.

This seems like another case of managers and politicians not appreciating the intense interpersonal aspects of medicine.  Physicians are all not foot soldiers just waiting for the next assignment from a policy maker.  Physicians have probably carefully selected the type of practice they want to be in and there are more than the technical aspects of the speciality that were considered.  It takes a unique skill set to treat people with addictions.  Treating and maintaining an opioid addict in treatment long enough with buprenorphine maintenance for them to realize any benefit is a very unique skill.  Being affiliated with other buprenorphine prescribers is also a necessity to provide cross coverage for patients.  Speciality care centers for addiction seem like an idea to me that does not get a lot of consideration.  Trying to run a buprenorphine maintenance program in a practice environment that is rationed to the degree it currently is does not seem feasible to me.  Adding buprenorphine maintenance as just another task for a busy primary care physician practicing primary care medicine is not likely to work.  It should be obvious that these physicians have  more than enough to do right now.

There is a lot more to it than increasing the maximum numbers of opioid addicted patients on buprenorphine maintenance and trying to treat as many people as possible.  The data from this paper illustrates that.  There is also the issue of the preventing the pool of opioid users from increasing while trying to treat those who are currently dependent on these drugs.  That seems like the best long term option to me.

Addressing this complicated problem takes more than a licensed buprenorphine prescribing physician sitting behind a desk who is willing to prescribe it.  It takes better infrastructure including managers who are enlightened enough to get that physician the kind of resources they need to do the work.  I never hear politicians or policymakers talking about that.


George Dawson, MD, DFAPA


Reference:

1: Stein BD, Sorbero M, Dick AW, Pacula RL, Burns RM, Gordon AJ. Physician Capacity to Treat Opioid Use Disorder With Buprenorphine-Assisted Treatment. JAMA. 2016 Sep 20;316(11):1211-1212. doi: 10.1001/jama.2016.10542. PubMed PMID: 27654608.


        

A Letter From The Surgeon General

Like most physicians in the United States, I got a letter from US Surgeon General Vivek H. Murthy, MD last week.  The focus of the letter was recruiting the assistance of physicians in solving what he describes as "an urgent health care crisis facing America: the opioid epidemic."  As an addiction psychiatrist about one out of every three new patients that I see is addicted to opioids.  I have been lecturing on this topic for 6 years now, so I have more than a passing interest in what the SG has to say.  I have to say that Dr. Murthy wrote an excellent letter.  I was particularly impressed with his second paragraph describing how the was a combination of good intentions to treat pain and aggressive marketing by pharmaceutical companies and the single most important sentence in the letter:

"Many of us were taught-incorrectly-that opioids are not addictive when prescribed for legitimate pain."

Since I was already out practicing for about a decade at the time, I was spared that initiative.  I never assumed that opioids were not addictive, only that some people were more predisposed to addiction than others and that some had such strong adverse effects that they were very unlikely to become addicted.  But in routine psychiatric practice, even before the epidemic it was common to see patients who demanded increasing amounts of addictive drugs or who were hospitalized for adverse effects.  I had treated numerous people who appeared to have dementia, but were longstanding users of opioids, benzodiazepines, and even older sedative hypnotics.

Dr. Murthy goes on to detail the costs in terms of 2 million people with prescription opioid disorder, increasing heroin use, and increasing numbers of cases of HIV and hepatitis C.  He acknowledges that treating pain with opioids and finding the correct balance between analgesia and addiction will not be easy.  He encourages physicians to take the pledge to turn the tide on the opioid epidemic at www.TurnTheTideRx.org and reading the enclosed pocket card to the CDC Opioid Prescribing Guideline.  He also encourages physicians to approach addiction as a chronic illness rather than a moral failing.  That will probably result in some blowback from the addiction is not a disease crowd.  I hope that it is clear from my previous postings that in popular surveys, most people consider addiction to be a disease.  At the scientific level, I think it makes the most sense.  A lot of the confusion in this area comes from a lack of appreciation about how substance use disorders are stratified.  Volkow came up with a good definition in a New England Journal of Medicine paper earlier this year (1) - separating substance use disorders in general from addiction and defining addiction as severe DSM-5 substance use disorders. (the DSM-5 refrains from using the term addiction).

The enclosed card entitled "Prescribing Opioids For Chronic Pain" touches on a few of the high points.  My section by section critique follows (the entire card is below in the supplementary section for review).  Section 1 focuses on pain ratings using the old 0  to 10 scale where 10 is the "worst pain you can imagine".  The unstated problem with that approach is that it is not quantitative and cannot be taken in isolation.  There are people for example where this rating is completely unreliable.  Section 2 is a consideration of non-opioid therapies.  It lists the usual medication prescribed for chronic pain.  The problem here is that acute pain is often an entry point for addiction.  There are many people getting opioids like oxycodone and hydrocodone for what used to be considered trivial injuries, like an uncomplicated ankle sprain.  The  other acute pain entry point for addiction is post operative pain.  There have been studies that show a significant number of patients are still taking opioids a year after their surgical procedure.  It is common for me to interview very young patients who were given opioids for trivial injuries or surgery who became addicted to these drugs.  Physicians need to be very clear on appropriate pain treatments and not offer choices.  For example,  I was told by a friend that he was in a situation where patients were offered acetaminophen, ibuprofen, oxycodone, or oxymorphone.  This is exactly the wrong way to approach the treatment of pain.  In a culture where many people consider themselves to be drug savvy - the overwhelming choice will always be the most euphoria producing opioid.

 Section 3 is a discussion of the treatment plan.  Treatment contracts can be useful here, because most patients need more than a discussion.  They need a document that they can refer to.  It also gives the physician clear anchor points that can be used when discussing a taper or need to discontinue the medication.  Section 4 involves the complicated assessment of harm and misuse.  For most physicians this means the capability to expand their diagnostic capacity from the primary condition and the associated pain disorder to being able to make the diagnosis of addiction.  In some cases there are clear markers (toxicology screens), but in many cases, the patient has developed an addiction as a direct result of the physician's prescription and the line between therapeutic use and addiction is less clear.

The card also provides clear examples of milligram morphine equivalents (MMEs).  This is a term used frequently in the research literature.  When comparing patients on different opioids it is useful to convert whatever opioid they are taking to MMEs.  Mortality and morbidity with opioid prescriptions are generally associated with daily doses greater than 90-100 MME range.  The card points out that this is about 90 mg of hydrocodone or 18 tablets of hydrocodone/acetaminophen 5/300 or 60 mg of oxycodone or 4 tablets of oxycodone sustained release 15 mg.  In patients with addictions it is common to see chronic use of 120-240 mg oxycodone per day.

The card provides advice on starting low and going slow with the dose escalation as well as a suggested taper of 10% per week.  It suggests limited supplies, much more limited for acute pain.  It cautions against prescribing opioids and benzodiazepines concurrently - a practice that remains all too common.  A sentence about how that happens might be useful.  Chronic pain is typically associated with anxiety, depression, and insomnia.  Patients typically are focused on symptomatic relief in all three areas.  That can result not only in benzodiazepine prescriptions but also the prescription of cross tolerant sleep medication like zolpidem or eszopiclone.  Another worse case scenario is the patient using extra opioids for treating these associated symptoms and that is very problematic.  Educating patients about all of these contingencies easily exceeds the time that most primary care physicians have to spend with people.  That may be another reason to have ample documentation available to assist physicians.  There also needs to be a complete discussion of side effects and adverse effects from opioids.

The card transitions into treating an opioid use disorder with medication-assisted treatment like methadone, buprenorphine, or naltrexone.  At this point, I think that the expertise of most primary care physicians has been exceeded and they are looking for referrals to treat the addiction.  I think that the context of care needs to change.  It is very difficult to be in a primary care setting focused on pain as the disorder one week and then transition to addiction care the next.  Most patients will be unable to make that transition in the same clinic.  The idea of offering naloxone for those with high overdose potential on the same card is also confusing.  I could see how it might result in patients being treated for pain and getting prescribed opioids also getting naloxone.  I think that naloxone is more appropriately used with a defined addiction and plan to address the addiction.  The best approach to prevent oversedation and cognitive side effects is close monitoring and gradual dose increases.

All things considered this was a good first effort by the Surgeon General.  I would like to see him become active in changing the cultural attitudes in the US about opioids.  There is a myth that opioids are the magic bullet for pain relief and that is not true especially for chronic pain where the effects are modest and not typically better than non-opioids.  There is a large segment of the American culture that also values getting high and opioids are always discussed from that perspective.  Americans hoard opioid medications and give them away and trade them with other people for various reasons.  When a medication becomes an urban legend like opioids have - it is like the old travelling medicine shows.  Opioids are good for whatever ails you and they make you feel good as a useful side effect.

Countering all of those cultural biases about opioids is a big job - but I am reminded of Surgeon General Koop and his approach to altering American biases about tobacco smoke.                   




George Dawson, MD, DFAPA


References:  

1: Volkow ND, Koob GF, McLellan AT. Neurobiologic Advances from the Brain Disease Model of Addiction. N Engl J Med. 2016 Jan 28;374(4):363-71. doi: 10.1056/NEJMra1511480. Review. PubMed PMID: 26816013. (full text).


Supplementary:

TurnTheTideRx Pocket Card as graphics below.  You can also download the actual card as a pdf at this link:

AMA versus CDC Patient Education On Opioids

CDC Poster On Opioids For Chronic Pain

The easiest place to start the critique of the initiative to stop opioid overuse in this country is the patient information products for both the CDC and the AMA.  The CDC poster on this subject is shown above and is public domain.  There is more detailed patient information from the CDC at Guideline Information for Patients.  The AMA page on the same subject is at this link.  AMA web site materials are copyrighted and I did not think it was worth the effort to attempt to get that permission.   It is available free online.  How do these guidelines compare with one another and are they likely to be useful to patients?

On inspection they both seem to warn patients that there are potential health problems including addiction and death from taking opioids.  The CDC graphic advises  the patient to actively collaborate with their physician around any potential opioid prescription.  It suggests that the physician in this case will present a number of non-opioid options and a receptive patient will decide how to use them.  Apart from the 1 in 4 statistic it is almost a fairy tale approach to the problem of addiction.  Keep in mind that direct-to-consumer advertising these days frequently end with a staccato-like recitation of side effects "including death" and pharmaceutical companies are not deterred from adding that qualifier.  That suggests to me that these dire warnings are really not a deterrent to people looking for what appears to be a "cure" - at least in some cases.  The more detailed approach from the CDC guideline seems more reasonable, but both do not take into account unconscious factors on the part of both the patient and physician.  The AMA version is seriously watered down, but both lack realistic information about addiction works.

The real issue with opioids is not that 1 in 4 people end up addicted to them.  That 1 in 4 number is after all an intent-to-treat number.  There are probably at least that many people who don't tolerate opioids at all, even on an acute basis.  Taking those people out, bumps up the number of potentially addicted to 1 in 3.  The real problem here is how the addiction occurs and the implications for primary and secondary prevention.  I can tell anyone who cares to listen that the secondary prevention aspect of opioid addiction is a long and arduous process, with no guarantee of a cure at the end of it.  Imagine that you have just started a family and started out in the workplace when the addiction occurs.  Contrary to all of the hype about medication assisted treatment with buprenorphine or naltrexone, this kind of treatment does not work well for everyone.  Addiction to an opioid may require that you participate in some form of education based treatment for up to three months or take long absences from your work and family to live in sober structured environments.  The structured environments are costly and the quality of these settings cannot be assured.  What the AMA and CDC references do not show is that if you have an addiction - you might be in a very expensive treatment program and still not be interested in stopping the opiate.  You may not feel ready to quit after one or more of these treatments.  The real danger of an addiction is that it alters your conscious state to continue the addiction, even in an environment where you are supposed to be learning how to get sober and maintain sobriety.

The AMA and CDC resources are short on this aspect of opioid addiction.  These pages should tell people a couple of other things aimed at preventing addiction rather than recognizing addiction and trying to treat it after it happens.  Here are the bullet points:

1.  Practically all people at-risk know it after they have taken the first few doses of medication.  The opioid makes them feel euphoric or ecstatic.  Contrary to the popular image of heroin addicts falling asleep, the at-risk population is energized and may feel like they have become more productive than they have ever been.  That response establishes a dangerous link between productivity and opioid use.  The at-risk population also has an enhanced perception of themselves.  They may suddenly perceive themselves as having become the person they always wanted to be.  That can include the perception of a number of positive personal qualities including confidence, intelligence, and creativity.  All of these reinforcing qualities disappear once tolerance to the drug occurs.

2.  People at-risk may notice that long standing anxiety, insomnia or depression is suddenly gone.  As an example, there are many people with social anxiety in childhood and early adult life.  Social anxiety is a condition where the person is overly concerned about being judged when they are out in public.  The associated concerns may be that they will be embarrassed or humiliated.  There is often an associated performance anxiety in certain situations.  This part of the at-risk population may notice that all of those concerns are completely gone when they start taking opioids.  All of these reinforcing qualities disappear once tolerance to the drug occurs and anxiety, depression, and insomnia recur (often amplified) during withdrawal and detoxification.

3.   The concept that opioids are medications that can reinforce their own use whether or not they actually work for pain is a difficult one to grasp.  In other words, the at-risk population may want to keep taking opioids even in cases where they do absolutely nothing to alleviate pain.  In this case it is not a question of tolerance to the analgesic effects of opioids.  The opioids did not work in the first place.  Opioids are only moderately effective for chronic pain in the first place and those effects are on par with antidepressants and anticonvulsants like gabapentin.

4.  Opioids can change your baseline personality and cause you to do things that you ordinarily would never have done.   Once an addiction has been established decision-making is in the service of maintaining the addiction.  That can include any number of legal and moral decisions that that involve the people who are closest to the person with the addiction.  The repercussions of these acts are not fully appreciated until the person is detoxified and is sober from the opioid.

5.  Opioids are legendary in the American culture.  The American culture strongly reinforces the place of intoxicants in the lives of even average Americans.  Intoxicants are in the literature, the media, and even day-to-day conversations.  People tend to hoard their unused opioids, exchange them with their friends and family, and talk about the effect of these drugs with their neighbors.  To illustrate, an acquaintance of mine recently had arthroscopic surgery of the knee.  He was in a large post-op recovery area with 8 other people.  Nursing staff were approaching people and asking them what they wanted for pain relief.  The choices were hydromorphone (Dilaudid) - a potent opioid, oxycodone-acetaminophen (Percocet) - a less potent opioid, and ibuprofen - a non-opioid.  The vote in the recovery room was 8-0 in favor of hydromorphone.  That vote parallels the disproportionate increase in emergency department visits for complications from hydromorphone relative to all other opioids.   Of course there are many variables at play, but I am suggesting at least one of them is the reputation that hydromorphone has in American culture as a potent euphoria producing opioid.

6.  Part of the American legend is that opioids are the magic bullet for pain.  The corollary is that if the doctor would just give me enough of this drug - my pain would be gone.  The important distinction here is chronic pain.  Across large populations there is no medication that will get rid of chronic pain.  For many people, no treatment at all, treatment with a non-opioid medication, or treatment with a different modality like cognitive-behavioral therapy works much better.

There are all important points for people to know before they start taking opioids.  I think that a clinical trial is indicated to see if people with this information do better than those without it.  If I was designing that trial, I would have an intervention that advised people to stop taking the medication and call the physician immediately if they experienced any change in their conscious state like the ones I described in points 1, 2 or 3 above.

Stopping opioid addiction well before it is established is the preferred intervention.  There is certainly effective treatment once an addiction has been established but it can be long, expensive, difficult, and the outcome is never guaranteed.  Anyone who starts to take an opioid needs that level of transparency.



George Dawson, MD, DLFAPA         

Attribution:  The infographic at the top of this post is from the CDC web site and is reused per their general information about being in the public domain.  The poster is available at:
 http://www.cdc.gov/drugoverdose/pdf/guidelines_patients_poster-a.pdf