Stochastic Processes In Human Biology

I was reading an important research article recently and encountered a term that I had not see in a while.  That word was stochastic. Physical science and engineering undergraduates probably encounter these words with different frequencies - most often as the expression stochastic process. As a chemistry and biology major, the main contact I had with the term was in what is typically considered the most mathematical of undergraduate chemistry courses - Physical Chemistry (PChem).  In the days I was an undergraduate we used a text by Moore.  In striving to stay in touch with the field I got a copy of a more current PChem text by Atkins several years ago.  The main reference to stochastic processes in both is the random walk problem.  In Moore it is in the problem set for the chapter on Kinetic Theory and and in Atkins it is in a separate supplement at the end.  That supplement is entitled Random Walk, illustrates how a random walk in one dimension can be used to derive an equation that estimates the probability of a particle being at a distance from the origin in a specified time during diffusion.  I won't include the equation here since there are a number of books and online sites where the derivation is available.

The authors of the research article were using it to describe a component of neuronal activity in the reward center of rats.  In their discussion of the term, they point out that brain complexity precludes the prediction of final outcomes from initial states. In the paper the authors were faced with explaining why a specific population of mice continued to self-stimulate dopaminergic neurons in the ventral tegmental area (VTA) via a optogenetic dopamine- neuron self-stimulation (oDASS) via an optic fiber despite punishment while another group of mice did not.  The details are included in the graphic at the top of this post.  To quote the authors on this phenomenon:

"Why only a fraction of mice lose control remains to be determined; the emergence of the two groups is even more surprising given the high degree of genetic homogeneity of the mouse line used here (our Dat^cre (also known as Slc6a3^cre) mice were backcrossed for more than ten generations into the C57BL/6J mouse line), and may reflect a case of stochastic individuality" (p. 320)

One of the key elements of this type of experimentation is minimizing variance form genetic and environmental factors.  The mice used in this experiment are inbred for several generations and in this case had a homozygous knock-in variation for dopamine transporter (DAT).  Colonies are developed to raise heterozygous mice with a greater expression of DAT for experimentation on these systems.  The idea behind backcrossing the mice for more than ten generations reduces the phenotypic variation but as noted in reference 2, there have been 30 years of experimentation of inbreeding mice and that reduces the phenotypic variance by 20-30%.  Although the C57BL/6J mouse line has its DNA characterized - I could not find any numbers for shared DNA on an individual to individual mouse basis.  As an example, in humans the following percentages of shared DNA would be expected identical twins (100%), parent-child (50%), grandparent-grandchild (25%), and first cousins (7.3-13.8%).

The experiment looked at these mice bred for a low degree of phenotypic variation who were all rained in similar environments.  All of the mice were trained for oDASS and then  subjected to foot shock as a punishment.  As noted in the graphic, 60% persevered despite the punishment and 40% renounced or had a marked decrease in oDASS after punishment. Both of these responses were considered distinct behavioral phenotypes.  The underlying molecular mechanisms were also studied.

The paper by Honegger and de Bivort (2) takes a more detailed look at examples of stochasticity. From a behavioral standpoint, they define stochastic individuality as non-heritable inter-organism behavioral variation.  The lack of concordance between identical twins is cited as a prime example. Beyond genomics they argue that stochastic individuality implies that if we know all about the basis of a trait at the -omics level and all of the relevant environmental factors – the behaviors will remain "beyond reliable prediction".  They review some examples from the animal kingdom. Marbled crayfish and pea aphids reproduce by apomictic thelytoky - that is all of the individuals are female and reproduction is clonal - therefore all individuals have the same genome.  Despite this individual display significant variation in locomotion and social behavior. They consider nutritional variances, self reinforcing circuits involving nutrition and behavior, and variation in biophysical developmental processes as possible mechanisms.  In the case of mice, highly inbred mice raised in the same environment vary significantly in their exploration of the environment. Individual mice that actively explore the environment have more robust hippocampal neurogenesis.

The authors detail and number of possible mechanisms underlying stochastic individuality including:

1.  A small number of effects at the molecular level promotes stochasticity.  Random fluctuations in RNA polymerase binding to DNA over time leads to fluctuating mRNA in the cell over time. There are also a host of possible mechanisms operating on small gene sets that lead to large combinations of possible outcomes.  An example given is T-cell biology in humans.  T-cells are essential for normal immunity in humans and the system can use a number of genetic mechanisms to generate a a very large number of T-cell receptor types (1015 to 1020 ) from a small number of genes (4).  The authors of this article discuss the fact that T-cell receptor diversity cannot be estimated by a priori assumptions suggesting this is a stochastic rather than deterministic process.

2.  Positive feedback in gene networks amplify fluctuations and can cause jumping between discrete states or bistability.  An example from the literature is cell quiescence, and there is thought to be a stochastic process involving a specific protein (5,6) that leads to the transition from active proliferation ( a number of states) to quiescence and back again.  

3.  Biological processes are systems that are non-linear, multidimensional, and have significant feedback and therefore are often chaotic.  Initial small differences will be amplified.  There are several disorders that occur with different concordance in identical twins (seizure disorders, cardiac arrhythmias) that could occur as the consequence of this process.  Biological systems that move large amounts of information across these systems are most susceptible.

4.  Somatic mosaicism – as cellular differentiation and proliferation occur genomic alteration can occur in new cells or their progeny. Transposons are active mobile DNA elements that can excise and re-insert into new positions in the genome leading to different cell genetics and tissues from the same progenitor cells.  In my current neurobiology lecture I discuss various level of brain complexity and give examples of 90 subtypes of potassium channels and significant numbers of vesicle trafficking proteins (7) in neurons.  Wilhelm, et al (7) reconstruct a 3D model of a synapse that contains 60 different in varying copy numbers. In the supplementary data they investigate a total of 100 different synaptic proteins and show that the copy numbers of each protein vary from 10 to 22,000 (Fig. S5).

The complexity of the synaptic proteins and their number may seem impressive and have the complexity to produce an apparent stochastic result. Looking at what might happen if these proteins are all modifiable by one of the mechanisms in the Honegger and de Bivort paper is more impressive.  The authors discuss alternative gene splice forms using a Drosophila example.  Proteins are typically formed in eukaryotic cells when the exon portions of the gene are cut and spliced from the intron or noncoding segment of a DNA or corresponding RNA transcript. Alternative splicing involves splicing that occurs in a way that some segments are altered or skipped. The result is multiple proteins being encoded by the same gene. A few examples are illustrated in the following graphic.

  

The nervous system implications of alternative splicing include recognizing that this occurs at every level of neuronal organization (8) and it has already been implicated in neurological diseases like amyotropic lateral sclerosis (ALS).  To get a quick look at what research may have already been done in this area I surveyed Medline for references to "alternative splicing" and "protein isoforms" for all of the neuronal proteins listed in the table of neuronal proteins listed in table S2 from reference 7.  As noted in the table there are probably over a thousand references unevenly distributed across these proteins indicating a significant amount of research on both the mechanism and classification of neuronal protein isoforms - many of which impact neuronal function and may be responsible for stochastic outcomes.

Research On Neuronal Protein Alternative Splicing and Isoforms
Protein	Alternative Splicing references?	"Protein Isoforms"[MeSH Terms] + Protein references?
SNAP 25	+	+
VAMP 2	+	+
α-SNAP	+	+
α/β-Synuclein	+	+
AP 180	+	+
AP 2 (mu2)	+	+
CALM	+	+
Calmodulin	+	+
Clathrin heavy chain	+	+
Clathrin light chain	+	+
Complexin 1,2	-	+
CSP	-	+
Doc2A/B	-	-
Dynamin 1,2,3	-	+
Endophilin I,II,III	-	+
Epsin 1	-	+
Hsc70	-	+
Intersectin 1	+	+
Munc13a	-	-
Munc18a	-	+
NSF	+	+
PIPKIγ	-	+
Rab3	+	+
Rab5a	-	+
Rab7a	-	+
Septin5	+	+
SGIP1	-	-
Synapsin I.II	+	+
Syndapin 1	+	+

At this point I am wrapping up this post with a list of stochastic mechanisms to follow in subsequent posts.  This is an important concept for psychiatrists interested in individual differences in behavior and well as unique conscious states to know about. It has the potential for greatly increasing the explanatory power of why there is so much heterogeneity in presentations of illness and outcomes.  It has the potential for providing a clearer understanding of the neurobiological substrates of behavior.  The distinct behavioral phenotypes in the experiment noted in the beginning of this post is a clear case in point.


George Dawson, MD, DFAPA




References:

1: Pascoli V, Hiver A, Van Zessen R, Loureiro M, Achargui R, Harada M, Flakowski J, Lüscher C. Stochastic synaptic plasticity underlying compulsion in a model of addiction. Nature. 2018 Dec;564(7736):366-371. doi: 10.1038/s41586-018-0789-4. Epub 2018 Dec 19. PubMed PMID: 30568192.

2: Honegger K, de Bivort B. Stochasticity, individuality and behavior. Curr Biol. 2018 Jan 8;28(1):R8-R12. doi: 10.1016/j.cub.2017.11.058. PubMed PMID: 29316423.

3: Ponomarenko EA, Poverennaya EV, Ilgisonis EV, Pyatnitskiy MA, Kopylov AT, Zgoda VG, Lisitsa AV, Archakov AI. The Size of the Human Proteome: The Width and Depth. Int J Anal Chem. 2016;2016:7436849. doi: 10.1155/2016/7436849. Epub 2016 May 19. Review. PubMed PMID: 27298622.

4: Laydon DJ, Bangham CR, Asquith B. Estimating T-cell repertoire diversity:limitations of classical estimators and a new approach. Philos Trans R Soc Lond B Biol Sci. 2015 Aug 19;370(1675). pii: 20140291. doi: 10.1098/rstb.2014.0291. Review. PubMed PMID: 26150657.

5: Yao G. Modelling mammalian cellular quiescence. Interface Focus. 2014 Jun6;4(3):20130074. doi: 10.1098/rsfs.2013.0074. Review. PubMed PMID: 24904737.

6: Lee TJ, Yao G, Bennett DC, Nevins JR, You L. Stochastic E2F activation andreconciliation of phenomenological cell-cycle models. PLoS Biol. 2010 Sep 21;8(9). pii: e1000488. doi: 10.1371/journal.pbio.1000488. PubMed PMID: 20877711.

7:  Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, KooSJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884. PubMed PMID:24876496.

8: Vuong CK, Black DL, Zheng S. The neurogenetics of alternative splicing. NatRev Neurosci. 2016 May;17(5):265-81. doi: 10.1038/nrn.2016.27. Review. PubMedPMID: 27094079.

Supplementary:

The Kyoto Encyclopedia of Genes and Genomes (KEGG) currently lists 40 alternative splicing factors. Link

Graphics Credit:

1:  Top graphic -> me.

2:  Alternate splicing graphic from VisiScience per their purchasing agreement.

Click on either graphic to enlarge.

The Abuse Potential of Gabapentinoids

I first started prescribing gabapentin in the 1990s, as part of an early attempt to see if it worked for bipolar disorder.  It was an off-label approach and did not have that indication.  At the time anticonvulsant approaches to bipolar disorder (valproate, carbamazepine) were being heavily used.  I was following a number of people who could not take lithium and on anticonvulsants and they seemed to do surprisingly well.  Gabapentin seemed to have significant advantages in terms of toxicity, it was well  tolerated by most people.  Unfortunately, it was completely ineffective for bipolar disorder and I stopped trying it almost immediately.

The next off label application that surfaced was for chronic pain.  Any psychiatrist is exposed to a number of patients with chronic pain or chronic pain and addictions, and it became apparent that it was being used successfully for chronic back pain, chronic headaches, and post herpetic neuralgia.  Over the next decade, gabapentin and then pregabalin was prescribed for chronic pain indications and people seemed to do reasonably well with it - even at relatively high doses.

At some point, physicians working in detox and the addiction field started to use gabapentinoids for chronic pain, anxiety, and withdrawal.  It is not uncommon to see patient with all of these problems who is not able to tolerate antidepressants for those symptoms or who needs more immediate relief.  In fact, in residential addiction treatment it is common to see patients come in on high doses of gabapentin for chronic back pain.   They are there for treatment of an opioid use disorder, but during that time have not escalated the gabapentin dose.

In the literature reports of gabapentin misuse have been surfacing over the past 5 years (1-7).  A large review (4) suggests that 1.3% of the treated population is at risk for gabapentinoid misuse with the number being much higher is some populations such as opioid users.  There is a report (3) that patients with opioid use disorder will attempt to augment the eurphorigenic effect of methadone in a similar way that they use benzodiazepines.  Benzodiazepine use with methadone in methadone maintenance clinics is a chronic and at times lethal problem.  There is a report from Norway (5) that gabapentinoids may be useful is reducing benzodiazepine use.  The report generally suggests that the abuse potential is low and greater for pregabalin than gabapentin.  There is an insurance database report (6) that looks at an overuse metric comparing gabapentinoids to other abused drugs.  Goodman and Brett (7) comment on the epidemiology of gabapentinoid prescribing, specifically an increase in gabapentin prescriptions from 39 million in 2012 to 64 million in 2016 with an associated doubling in the sales of pregabalin during the same period.  They attribute the increase to attempts to treat chronic pain without opioids in primary care, suboptimal non-opioid medications (acetaminophen and NSAIDs). They cite mixed evidence in clinical trials, side effects, misuse or diversion, and an excessive focus on pharmacological measures for pain as being concerns.       

Are there biases in these report?  There certainly are.  I don't have access to the full text of the most comprehensive paper (2), but I would be interested in looking at the actual numerator and denominator for their numbers and how much was based on actual pharmacovigiliance/pharmacosurveillance as opposed to case reports, case series and reports of complications.  The other issue is that all of these papers seem to come from the same publisher.  I have not encountered that before.

The only study that I could find that looked at the direct question of concomitant use of opioids and gabapentin came from Canada (8).  It studies a large group of patients on a database that records the prescriptions and looked at all opioid users that died of opioid related causes between 1997 - 2013.  The big picture is that there were a total of 2,914,971 opioid users during the study time frame and 6,745 died of opioid related causes.  Then by selection criteria they identified 1,256 cases and matched them to 4,619 controls. They defined gabapentin exposure as concomitant gabapentin use in the 120 days preceding the index date.  They also looked for a dose response relationship of gabapentin doses considered as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily).  They also did a comparison with nonsteroidal anti-inflammatory drugs (NSAIDs) used as an adjunctive pain medication instead of gabapentin.  Their results are summarized in the following tables excerpted directly from the article (click to enlarge):

 
As noted from the data and analysis, 12.3% of the controls and 6.8% of the cases were prescribed gabapentin in the 120 days, representing a 50% increased risk of death in the gabapentin treated cases.  In the case/control comparison both groups have roughly the same levels of mental illness but the case group had higher utilization of antidepressants (all types), benzodiazepines, and other drugs/CNS depressants. They were also taking substantially more high dose opioid therapy (>200 MME).  Higher dose gabapentin nearly doubled the risk. There was no added effect from NSAID use.  The authors conclude that caution needs to be exercised in deciding to prescribe this combination (opioids + gabapentin) and that if that decision is made it needs to be carefully monitored.  From my perspective I had some concerns about the controlling for benzodiazepine use in the case/control comparison and did not see any risk attributable to benzodiazepines.  The authors do cite a reference that led to FDA warnings about the benzodiazepine-opioid combination. 

Given the concerns about gabapentin why use it at all?  The main reason is that it is effective for some of the most difficult problems in medicine.  It is very difficult to see people with extreme anxiety and insomnia go for weeks without sleep and experience continuous panic attacks all day long.  When a person stops taking benzodiazepines that they have been taking for years that is a frequent result.  The same is true for people who have decided to stop drinking and suddenly have very high levels of anxiety and insomnia now that their baseline anxiety is back.  More to the point, unless something can be done to provide them with timely relief, relapse to drug and alcohol use is certain.  Finally does high levels of abuse by some patients with addictions suggest that the medication is unsafe?  It is probably safer then other medications in this population and extremely safe outside of those populations.  In either case safety depends on whether there is a physician involved or the medication is acquired from nonmedical sources.   

Standard practice with gabapentin should be to tell all patients (in addition to the usual discussion and detailed information) the following information.  I point out here that I do not prescribe pregabalin:

1.  Take this medication exactly as it is prescribed.
2.  Do not accelerate the dose of the medication.
3.  Do not mix this drug with alcohol or any other intoxicants or street drugs.  If a relapse occurs call to discuss and set up a plan as soon as possible.
4.  Do not stop the medication abruptly it needs to be slowly tapered.  There is a seizure risk if it is not.
5.  This medication is potentially addictive to some people. If you notice any tendency to take more of this medication than prescribed contact me immediately.
6.  This medication is monitored on the state Prescription Monitoring Program and all prescriptions are recorded even though it is not technically a scheduled drug at this time.

At least that is the way that I think it should be handled.  If I was still seeing a lot of patients with chronic pain on moderate to high doses of opioids I would add in a line or two about the the Canadian study (9) and greater chances of death from the gabapentin + opioid combination.  In my current practice, psychiatric treatment is split off from buprenorphine detox and maintenance treatment - but I still see a lot of patients on buprenorphine + gabapentin and can attest to the fact that in a controlled environment we have not observed the complications suggested by the Canadian study over a period of months.  None of these patients receive benzodiazepines or sedative hypnotics beyond a period of detox.  In fact, doing that study might be a significant contribution to the research.  It also probably means that those patients when they are discharged should hear that the risk of taking that combination may increase substantially in the outpatient setting.

There is plenty of politics and confusion surrounding the gabapentinoids issue.  It should not be surprising that this medication is showing up in the toxicology of opioid overdose victims. It should not be surprising that some people try to get "high" on it, even though the people doing that do not have typical ideas about the utility of medications. It should not be surprising that people try to use gabapentin like benzodiazepines to augment the effect of what they are using to get high especially opioids.  It should not be surprising that when some people decide to stop buprenorphine or methadone that they will buy somebody's gabapentin to try to treat withdrawal effects.  It should not be surprising that in some areas it is currency on the street (What can I get for a month's worth of gabapentin?).  It should not be surprising that it has become a political football in the social media on pain ("See it's not opioids as the problem - it is gabapentin") or the social media on weed ("See these are Big Pharma solutions, marijuana is much safer").  It should not be surprising that you can read about it on drug culture web sites where everyone is an expert pharmacologist and provides you with anonymous advice on how to get high. It should not be surprising that you can buy it online and have it delivered to your door, although you can never really be certain that it is the same stuff you get at Walgreens.  I am always amazed at how easy it is to sell some Americans drugs, if they think there is the slightest possible chance they can get high on it. That is also why it should not be surprising that children and teens will take it out of medicine cabinets - use it to get high and brag about it even though there were probably not high at all.

The features about the gabapentinoids that make sense to me is that they are medically useful  and have low toxicity, for people with nearly impossible problems in desperate situations.  It is a less toxic drug on the street than those mentioned in the above paragraph. Even then these drugs need to be carefully prescribed and closely monitored.  And even then some people will escalate the dose. There are no perfect solutions in medicine and in this area in particular - nothing seems to be coming down the pike.  The probability statement is always - does the use of gabapentin result in more people with improved symptoms, better quality of life and less addiction?  At this time unless presented with compelling evidence I would say that it does with the qualifier that its application needs to be carefully done by a physician who knows what they are doing and is aware of the potential for misuse. In  the current era, that can all be subject to the next social media fad.

There is not a big push by the pharmaceutical industry at this time to discover a drug that has limited toxicity that can be used for severe chronic pain, insomnia, and anxiety associated with addictive disorders.  There is also the question of what medications are being used for these problems if not gabapentin.  The answer is atypical antipsychotics (mostly quetiapine), hydroxyzine (a first generation antihistamine), and clonidine (primary use is hypertension and opioid withdrawal).  If the comprehensive toxicology of overdoses is available I would expect to see these compounds listed.  In any search of drug interactions both quetiapine and hydroxyzine are flagged as potentially affecting cardiac conduction. Clonidine can cause hypotension if used excessively and rebound sympathetic symptoms (tachycardia, hypertension, diaphoresis).  Looking at that group of medications gabapentin would appear to have the preferred side effect profile.

There also appears to be a big push to make gabapentin a controlled substance according to the Controlled Substances Act (CSA).  Pregabalin is currently a Schedule V drug (see page 14) or considered to have the lowest abuse liability.  Getting on that list depends on how the DEA currently sees the addictive behavior towards gabapentin versus pregabalin.  Putting a drug on Schedule V will probably have no impact on how it is used in medical practice or out on the street.  The fact that pregabalin is ranked so lowly is a sign of regulatory opinion on abuse liability.

That's my current opinion on the topic.  I may add more to this post in the future or to a post I am working on about the basic science of gabapentinoids.


George Dawson, MD, DFAPA


References:

1:  Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014 Jun;28(6):491-6. doi: 10.1007/s40263-014-0164-4. Review. PubMed PMID: 24760436.

2:  Chiappini S, Schifano F. A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database. CNS Drugs. 2016 Jul;30(7):647-54. doi: 10.1007/s40263-016-0359-y. PubMed PMID:27312320.

3:  Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: a survey among substance misusers. Eur Addict Res. 2014;20(3):115-8. doi: 10.1159/000355268. Epub 2013 Oct 31. PubMed PMID: 24192603.

4:  Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017 Mar;77(4):403-426. doi: 10.1007/s40265-017-0700-x. Review. PubMed PMID: 28144823.

5: Smith, R. V., Havens, J. R., and Walsh, S. L. (2016) Gabapentin misuse, abuse and diversion: a systematic review. Addiction, 111: 1160–1174. doi: 10.1111/add.13324.

6: Bramness JG, Sandvik P, Engeland A, Skurtveit S. Does Pregabalin (Lyrica(®) ) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. Basic Clin Pharmacol Toxicol. 2010 Nov;107(5):883-6. doi: 10.1111/j.1742-7843.2010.00590.x. PubMed PMID: 22545971.

7: Peckham AM, Fairman KA, Sclar DA. Prevalence of Gabapentin Abuse: Comparison with Agents with Known Abuse Potential in a Commercially Insured US Population. Clin Drug Investig. 2017 Aug;37(8):763-773. doi: 10.1007/s40261-017-0530-3. PubMed PMID: 28451875.

8: Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017 Aug 3;377(5):411-414. doi: 10.1056/NEJMp1704633. PubMed PMID: 28767350.

9: Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W.  Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017 Oct 3;14(10):e1002396. doi: 10.1371/journal.pmed.1002396. eCollection 2017 Oct. PubMed PMID: 28972983; PubMed Central PMCID: PMC5626029.

Graphics Credit:


Figure 2 about is excerpted directly from the work in reference 8 above per the Creative Commons Attribution License.  The authors are listed as the copyright holders.


Supplementary:

Publication from the above content?  If you are a psychiatrist or pharmacologist and think you can rework the above article into a publication.  Contact me and let's write that paper!

The Most Important Decision In Your Life......

See Complete Reference Below

I thought a while about how to write this.   There are a lot of opinions out there about how a decision like this one should be philosophical or religious.  After practicing psychiatry for over 30 years I have to come down on the side of practical.  The most practical decision I think that anybody can make is to stop using intoxicants, at least to the point of intoxication.  I don't really care what your current intoxicant is.  It could be alcohol or cannabis or heroin.  Deciding to stop it will only improve your life and the lives of your family and friends for any number of reasons.  At this point I am a witness to the thousands of people who have stopped and seen those improvements.  I am also a witness to the unfortunate thousands of people who did not stop and ended up dead, incarcerated, homeless, chronically mentally ill, in nursing homes, or leading miserable lives.  I am not naive enough to think that my little argument here is going to make that much of a difference and will elaborate on that in the paragraphs that follow.

One counter issue that I want to address as early as possible because it is often used to short circuit arguments against intoxicants is what I consider an American pro-intoxicants argument.  It certainly can exist in other cultures, but I am restricting my comments to Americans because of the pervasive attitudes about intoxicants.  The most obvious attitude is alcohol and drug use as a rite of passage to adulthood.  This is a well documented phenomenon rationalized at several levels.  Common examples include: "If one is old enough to vote or go to war they are old enough to drink."  There is abundant current evidence that 18-21 year olds if anything are exposing brains that are neurodevelopmentally immature to the effects of alcohol and street drugs - often at toxic levels.  Rational arguments against exposure are not likely to have much of an impact on a population segment in the throes of the invulnerability of youth.  Even apart from the brain based argument, the driving and risk taking behavior of this group is well documented.  Adding intoxicants to the mix is not likely to alter those decisions in a positive way.

An extension of the rite of passage argument is the rights argument as in "Alcohol and tobacco are legal substances and therefore I have a right to use them."  There is no doubt that is true, but the right is limited.  Only people of a certain age can use these compounds and in the case of intoxicants that can affect public safety - their use is even more limited.  People who I have seen invoke the rights argument are generally not talking about limited rights.  The modern version of the rights argument is that "no one should have the right to tell me what I can put in my body.  On that basis all drugs should be legal and easily accessible".  A complementary argument is: "Alcohol and tobacco kill more people every year than (fill in favorite intoxicant here) and therefore I should be able to use it."  Another complementary argument that often gets more support is: "The War on Drugs is a complete failure.  All drugs should be legal and that way we can tax it and make a profit from it.  We can put the cartels out of business."  The rights argument frames an idyllic drug consuming society immune to the medical problems of acute intoxication and addiction as well as all of the associated social and legal problems.  Extreme arguments like this suggest to me that they are driven in part by desperation.  Of course intoxicants need to be regulated - we already have ample evidence of what happens when they are not.  The basic problem that they reinforce their own use at increasing levels cannot be ignored.  Tax on intoxicants is generally an unreliable revenue source when the total cost to the taxpayers for that intoxicant and the fact that revenue is diverted away from covering those costs.
  
A second cultural phenomenon is the use of intoxicants for celebrations.  Weddings, funerals, and various parties often result in the excessive consumption of alcohol. I attended a funeral where the clergyman addressed half of the audience and suggested that an AA meeting might be in order afterwards.  The deceased was probably a victim of excessive alcohol use.  Although alcohol remains predominant in many of these settings, since the 1970s second and third intoxicants are also common.  The relevant consideration is whether these celebrations can occur without the intoxicants.  Interestingly, that decision may come down to the cost of having an "open bar" versus less expensive alcohol on tap. 

A third consideration is the subculture of extreme use.  Many states are notorious for per capita alcohol consumption, binge drinking, and driving after drinking too much.  I don't think that the problem has been well studied, but growing up in a heavy drinking or using culture exposes anyone to early use and reinforcement that are both precursors to problematic use. 

There are several arguments in the popular media that seek to minimize the potential impact of drugs on your life.  Think about the counterarguments:



1.  If I don't have a diagnosis of alcoholism or drug addiction my pattern of using intoxicants is not a problem:

The most absurd presentation of this argument was the idea that a significant number of binge drinkers do not meet diagnostic criteria for alcohol use disorder.  I can't count the number of people who I know that have had their lives ruined or ended by a single drinking binge.  Many high schools in the US started a senior party strategy because so many students were killed around the time of graduation parties due to acute alcohol intoxication.  The drivers in these cases were not alcoholics.  They were high school seniors many of whom had limited exposure to alcohol before the fatal accident.  Binge drinking and acute intoxication is associated with a long line of accidental deaths, alcohol poisoning deaths, suicides, homicides, intimate partner violence, rapes, and other crimes.  All preventable by not binge drinking or more importantly getting intoxicated in the first place.  The same pattern follows every other intoxicant.  If you put yourself in a mentally compromised state in practically any setting - bad things will happen whether you have been diagnosed with a substance use disorder or not.

2.  Alcohol is a heart healthy beverage:

The CDC and the American Heart Association both recommend moderate intakes of alcohol and they define that as one standard drink of alcohol per day for women and one or two standard drinks for men.  This is based on data that shows that these amounts of alcohol may confer reduced risk for heart disease but that higher amounts increase risk.

3.  Intoxicants can be good for your health - some are natural medicines:

The great natural argument leaves a lot to be desired. It's like listening to that guy in a bar tell you that his doctor told him he could drink as much wine as he wanted because it was a natural beverage and then realizing that he is standing in a puddle of his own urine. Peak alcohol consumption in the US occurred at time when it was considered a medication in the early part of the 19th century.  The current best example is cannabis, a substance that has been around for at least 10 centuries and suddenly it is a miracle cure for everything.  The obvious question is why that wasn't noticed in that last 1,000 years. 

4.  Alcohol and drug use disorders are not diseases - it is a question of choice and therefore I have nothing to worry about:

Despite what you may read on some online blog, in opinion polls most people consider alcoholism and addictions to be diseases.  Almost everyone has had some contact with people who have these problems and they see that the usual negative consequences that cause most people to correct their behavior - have no effect on the addicted.  There is no or at least limited capacity for self correction.

5.  I am a libertarian and I believe that all intoxicants and drugs should be legal - I should be the only person deciding what goes into my body:

A familiar argument that ignores human history. The reason that there are controls on addictive drugs is because a significant part of the population will use them in an uncontrolled manner and that generally leads to a chaotic society with all of the costs of that chaos. The more free access there is - the more addiction and chaos.

This argument implies that everyone is the best judge of "what I put in my body" based on political beliefs. There is no evidence that is true.

6.  I am an adult and if I want to have a drink - I will have a drink:

That is a minor variation of the libertarian argument for non-libertarians.  It is basically a truism - yes of course unless you are prohibited by law (and some people are) you can have a drink.  Doing something basically because you can strikes me as a shallow argument. Looking at what happened during Prohibition, I think it is safe to say that the right to drink was preserved by a relatively vocal minority of people who want to drink.  They want to drink for the previously cited cultural reasons and in fact there were some famous exceptions to Prohibition that were based on purported religious ceremony and requirements for alcohol. 

A similar argument is that if a person wants to feel high "there is nothing wrong with that."  At a superficial level and strictly speaking that is true as long as the level of intoxication doesn't lead to medical, safety, or interpersonal problems. The larger question is whether there is something better to do. Let's define better as another recreation that leaves you better off than using intoxicants.  In that case walking around the block is better than getting stoned.

7.  It is part of my creative process:  

There are reviews and books written about how creative people have used drugs and alcohol to enhance their creative process.  These works are by their nature anecdotal.  I am unaware of any controlled sober group and their creative process but it is likely that they exist in large numbers.

8. I am self -medicating and need it to treat insomnia, anxiety, depression, and/or pain:

Self medication implies that intoxicants are actual treatments for these problems. If you talk to any person who uses this strategy - the amount of relief lasts for a few hours.  People tell me: "Look doc - if you can't get rid of this anxiety - I know how to get rid of it for a few hours."  Using alcohol, street drugs, or diverted prescription medications is usually a recipe for worsening symptoms and tolerance.  In that setting people often have the idea that more drugs will bring back the few hours of relief and there are always examples of associated catastrophes in the news. 

9.  The political argument that by allowing universal access to drugs - the cartels will be out out of business - 

Very common to hear that all drugs should be legalized and hear this argument in the next breath.  Most of the people making this argument seem naive to fact that black markets still exist with legal intoxicants.  In the WHO Global status report on alcohol and health 2014, 24.8% of the alcohol consumed was outside of government control.  In the US, it was 0.5 liters of a total of 9.2 liters per capita.  For tobacco the black market is somewhere between 8.5 and 21% of sales. In Colorado there is currently mixed concern about the possibility that drug traffickers are in plain sight, continuing to grow cannabis in remote areas and transport to other states, but reliable information is not available. In the case of heroin, the current impetus for its use is that it is 25% the cost of diverted pharmaceutical opioids.  In the worst case scenario of legalized opioids with no control is it realistic to consider governments regulating heroin at that low cost to consumers?  If not it is a recipe for continued uncontrolled black markets. 

10.  The "You are an prohibitionist" counterargument:

Whenever I present any of my arguments for avoiding intoxicants in the list above, there is the inevitably that some very angry guy accuses me of being a prohibitionist.  I don't know how much weight that ad hominem carries but I always find it amusing. If prohibition worked, I would not need to make these arguments.  My blog is one of the few places where you can see a graphic of how things went during prohibition and it obviously wasn't good.
 
Believe me - you can go through life without ever taking a drink, smoking a joint, snorting cocaine, or injecting heroin and not miss it.  The best case scenario is that it adds nothing to your quality of life.  It is also tempting to think that you have plenty of time to quit later.  With that plan many people either never quit or realize when they are 40 years old that they have been in a fog for 20 years.  Addictions sneak up on you and steal what should be your most productive years.

In fact none of the people with addictions who I talk to ever started out believing that one day they would end up with an alcohol or drug use problem.  Recognizing all of the defective arguments listed above is a good first step.  The most important ability to prevent addictions is self correcting abstinence.  If you wake up one day and realize you dodged a bullet when you were intoxicated, think long and hard about avoiding that situation again.

If you can't - you may have a serious problem.


George Dawson, MD, DFAPA



Supplementary:

Graphic at the top is from:

Lavallee RA, Yi H.  Surveillance Report #92: Apparent per capita alcohol consumption: national, state, and regional trends, 1977-2009.  US Department of Health and Human Services. Public Health Service.  August 2011.  Link.

Why Most People Don't Have A Mind For Medicine

The inspiration for this post was a story I just read about the "victims" of the crackdown on opioids.  A number of chronic pain patients were described who were only able to get pain relief from opioids.  They discussed being limited to arbitrary reductions in medications or monthly limits imposed by politicians.  In some cases the people taking pain medications were being treated like criminals.  They don't like being treated on the basis of people who are addicted to opioids.  I did a more extensive search and there are several articles out there like this.  The general tone of the article is that there are tens or millions of people out there with chronic pain and that since many of them need opioids for chronic pain aren't we overdoing it a little with the restriction on opioids?  Why should good people suffer just because some addicts misbehave and die?

Some of these articles attempt a semblance of balance.  They discuss the timeline of the opioid crisis based on policy changes and pharmaceutical marketing.  They may get the opinion of some experts than generally falls along polarizing lines.  In the end the reader is generally left with a definite viewpoint on what might be the right or wrong approach to chronic pain and the opioid crisis.  There is never an explicit statement about right or wrong approaches being the way we got into the opioid crisis in the first place.  Medicine is not a a field that you can generally approach with a pre-existing right or wrong bias - at least not for the majority of patients.

Most medical care is directed at a collection heterogeneous disorders spread across the entire population.  Each of these conditions has numerous etiologies and no clear cure.  That means from a medical standpoint it typically takes a number of trials to see if something works.  Since only a fraction of the target population responds to the intervention and a significant fraction of the target population does not tolerate it - the interventions are generally seen as being weak across the entire population.  That supports odd arguments like: "Antidepressants don't work" or "Beta blockers don't work for hypertension" or "Thiazide diuretics should always be the first line medications for hypertension".

It is also very tempting to look at the entire heterogeneous population and think: "Now we have a medication that can treat everybody.  This is the magic bullet for this disorder".  There are really very few medications that work that way.  The reason for the less than robust response blockbuster drugs is quite simple - a significant number of people typically do not respond or get side effects to the point that they want to discontinue the medication.   That negative response to medication is typically the main limitation when it comes to the overall effect of a medication on any population.  In my experience about 1/7 people cannot tolerate an SSRI type antidepressant medication due to side effects.  An addition 2/7 will not get an adequate therapeutic response.  On the other hand the 4/7 of the people that respond may feel much better and notice a complete remission of depression or anxiety symptoms.  Looking at the entire population the overall effect of the medication is not robust, but that does not mean that it might not be a life changing medication for some.

Opioids present a much different landscape because in many people they reinforce their own use irrespective of whether the medication works or gives that person significant side effects.  You read that correctly.  I have had people tell me directly that they got absolutely no pain relief from an opioid but they liked taking it so much they continued to get the prescription filled.  I have had people tell me that they got significant side effects from opioid medication but they kept taking it because they liked how it made them feel.  Keep in mind that there is always a range of these effects but I have never heard people describe these experiences with SSRI antidepressants.  The mere taking of an SSRI antidepressant does not reinforce continued use.      

This is the special dilemma with opioids and all medications that reinforce their own use (benzodiazepines, stimulants).  When a person says that they need to keep taking that medication - what does it really mean?  I will be the first to admit that they may need to take the medication and have treated chronic pain patients for years who were taking opioids.  They were still in pain to some degree but they also believed the opioid was providing them with some degree of relief.  The only visible sign that they could take opioids on a chronic basis was that they did not escalate the dose and did not get additional opioids or addictive drugs from other medical or non-medical sources.  The obvious question in this case is "Why don't you just increase the dose of opioid to get rid of the pain?"  The answer is that there is no medication - not even opioids that completely alleviate chronic pain.  I have had many acute pain sufferers tell me that they did not get much relief from acute pain with opiates until the non-specific effects like sleep took over.

Another factor to consider is that most chronic pain patients who come to addiction treatment centers feel markedly better and in less pain when they are tapered off opioids and placed on non-opioid medication for pain.  People are often surprised to hear that, but based on what I just said it should not be that surprising.  If you are taking a medication that will not completely eliminate chronic pain, has a lot of side effects, and biases  you into taking it and ignoring those side effects - how can you not feel better without it?

The final piece of the equation is addiction or severe opioid use disorder.  At this stage - the problem is compounded by the fact that a person needs to take the medication in order to function on a day by day basis.  If you happen to be a person with chronic pain - not being able to function in addition to the chronic pain puts you in an impossible situation.  That is especially true if you are escalating the dose of medication in order to try to recapture the original high, cope with an emotional state,  or  get some sleep.  In many of these situations the person will find themselves "cut off" from the clinic they attend because they have exceeded their prescribed amount of medications.  Because that precipitates acute withdrawal they may seek prescription medications from a non-medical source or start using heroin.

I hope that I have been able to convey the complexity of the situation with opioids for a chronic wide scale problem as opposed to other medications for similar problems.  The stimulus for this post is the usual swing in journalistic opinion with complex problems.  I was going to title the post: "Why journalists and politicians can't practice medicine".  Complex chronic problems in medicine cannot be oversimplified into binary solutions at this point in time.  Researchers are currently developing the tools that will allow us to identify subgroups in these populations and subject people to less trial and error.  At some time in the next 10 years, I expect that we will be able to rapidly identify who might be able to take opioids in a non-addictive manner and who will not be able to.  We might even have better medications for chronic pain that are safe and non-addictive by then.

In the meantime, a rhetorical approach casting some people as victims and  others as villains is unproductive and stigmatizing.  As I tell my students it is the difference between drawing inferences about people in a large city based on the amount of addiction there.  Twenty years ago in that large city children going to school would have to walk past three or four drug dealers.  As a result urban addiction rates were much higher than rural addiction rates.  Now that the rural kids have to walk past as many drug dealers, people in rural settings are addicted to heroin and dying of overdoses.  Exposure to drugs rather then moral superiority is the limiting factor.

To do well in medicine a physician needs to have good probabilistic thinking.  A lot of that process is acquired rather than learned on a rote basis.  Errors in this decision making process are almost guaranteed, but the only real problem are the physicians who seem to error all of the time.  That turns out to be a minority of physicians.  I expect that this group has difficulty managing both the treatment probabilities and interpersonal dynamics required to treat chronic pain, recognize addiction and implement the appropriate interventions.

One thing is for sure journalists, politicians, law enforcement, and insurance companies do not do a better job than the majority of physicians.  It is a major mistake to think otherwise.        



George Dawson, MD, DFAPA    





Supplementary:

Graphic is supposed to indicate that only a physicians with direct responsibility to the patient can appreciate the complexity of the situation especially when it comes to the nuances of addiction and chronic pain treatment.  It should be apparent that complexity can not be captured by rating scales.


Attribution:

Eyeball graphic is from Shutterstock "Untitled" per their standard agreement.