White Coat Underground

Whose demons?

“…It never was our guise 
To slight the poor, or aught humane despise: 
For Jove unfold our hospitable door, 
‘Tis Jove that sends the stranger and the poor…”

—Homer: The Odyssey, Translation by Alexander Pope

A few weeks ago, Drugmonkey wrote a piece about perceptions of drug users.  Specifically, the study looked at how mental health providers perceive people with substance use disorders depending on whether the patients were referred to being a “substance abuser” vs. having “a substance use disorder.”  These data revealed something interesting.  Among the mental health professionals:
…those assigned the “substance abuser” term … were significantly more in agreement with the notion that the character was personally culpable for his condition and more likely to agree that punitive measures be taken…

[...]


[they were more likely]…to convey internal causal attribution and personal culpability, a moral vs. medical solution, suggesting the character has volitional control and might be viewed as a “perpetrator”who is willfully engaging in the behavior and thus more deserving of punishment.


I would not be surprised if these results were reproducible in primary care physicians.  People with substance use disorders can be difficult to care for even before we layer on our own prejudices. Anecdotally speaking, substance abusers can be needy, stubborn, and narcissistic. They can behave inappropriately and show little respect for boundaries.  These behaviors set off a whole set of reciprocal behaviors in providers.  If a patient demands a narcotic medication, the reaction is often to become angry and say “no” without responding to the underlying pathology (not, that is, the pathology of the back pain, but the narcotic dependence).  

This phenomenon has been documented in various ways over the years but I’ve found little in recent literature examining physicians’ attitudes toward people with substance use disorders.  Today, though, I found an interesting article just published in the journal Addictive Behaviors which looked specifically at doctors’ attitudes toward prescribing opiates in patients with a history of substance abuse.  The study’s findings resonated with me, and I suspect they would with many doctors. 

One finding was that in persons with a history of substance abuse (PWHSA), doctors often considered them guilty until proven innocent, which in a way makes a certain amount of sense.  The patient, having shown themselves to be particularly susceptible to substance use disorders, is, in a sense, already “guilty”.  The question here is how will that scarlet letter affect their care.
In this study doctors expressed fears—reasonable ones, I think—of addiction and of diversion.  They looked at certain red flags in trying to predict inappropriate narcotic use, including doctor shopping, borrowing others’ opioids, reporting that their prescriptions were lost or stolen, and other traits that often mark a patient as a “danger” to the doctor.  
Also prominent was the concept of “genuine pain”, that is—presumably—pain caused by a clear pathological anatomic problem and something more subjective.  To me, this is where it gets interesting.
I don’t know if the red flags noted actually correlate with substance abuse.  I tend to believe that they do, but of course they could also be behaviors learned in response to not getting adequate pain treatment.  These studies bring up some common problems with the way we view substance use disorders: the temptation to blame SA on moral failings, and the splitting of medical problems into those of the mind vs. those of the body (and the implied volitional component of each).
Opioids and other narcotics do not affect only “the mind” or even the brain;  they have physiologically and anatomically diverse affects.  To call SA a “mind” problem is simply wrong.  And since there is no “mind” without “brain”, to speak of mind at all in this context only serves to further confuse the issue.  
We know that there are many simple behaviors over which we have variable control: breathing, muscle twitching, tics, yawning.  Opioid dependence is associated with many negative behaviors many of which are more complex than twitching, but may be under the same amount of control.
This morning I got up late.  My wife and kid weren’t feeling well, so I stayed home and hung out for a while.  I made myself a cup of good tea and read a bit.  I cuddled the kiddo, and eventually got ready for work.  As I pulled into the parking lot at the hospital I realized that I wasn’t feeling so great.  My head felt heavy, I felt a little dizzy and nauseated, and I was beginning to get a headache.  As the elevator stopped at every floor, I realized that I was also pretty irritable.
As I finished my rounds I realized I need my coffee—NOW.
I walked quickly back toward the elevators thinking about how I would order my coffee, about how quickly I could get downstairs for my coffee, about what my coffee would taste like.  I worried that I wouldn’t get my coffee quickly enough to stave off my headache. 
Empathy is a critical part of medicine.  We can’t (and probably shouldn’t) completely empathize with all of our patients, but we must understand that behaviors and motivations are complex.  We may be right to be suspicious of the “dog ate my Vicodin” guy.  It may turn out that we have little to offer him.  But his behavior looks different when you consider its complexity.  
Service is a considerable art of medicine, and while we aren’t obliged to serve everyone in every situation, learning to try is part of the deal.  

References

Kelly, J., & Westerhoff, C. (2009). Does it matter how we refer to individuals with substance-related conditions? A randomized study of two commonly used terms☆ International Journal of Drug Policy DOI: 10.1016/j.drugpo.2009.10.010

Baldacchino A, Gilchrist G, Fleming R, & Bannister J (2009). Guilty until proven innocent: A qualitative study of the management of chronic non-cancer pain among patients with a history of substance abuse. Addictive behaviors PMID: 19897313

Comments

  1. #1 DrugMonkey
    January 27, 2010

    I think the fact that you recognize your own caffeine dependency is a major part of the empathy battle. Many of us are totally dependent on caffeine and to some extent recognize this. Yet because coffee and tea consumption is such a socially acceptable part of our landscape, we often do not draw the appropriate parallels with dependence on illicit drugs.

  2. #2 History Punk
    January 27, 2010

    Any idea how pressure from the DEA and other such agencies influences treatment of possible/confirmed illict drug users?

  3. #3 PalMD
    January 27, 2010

    I have no idea. My only contact with the DEA is when I renew my license.

  4. #4 leigh
    January 27, 2010

    i am impressed, Pal.

  5. #5 MatthewF
    January 27, 2010

    As Enoch Root would say, “Morphiumsuchtig”/”Morphine Seeky”, not a “Morphine Addict”.

  6. #6 synapse
    January 28, 2010

    That’s why I quit coffee. I had migraine for a week and occasional cravings for over a year, but I have fewer headaches and feel better about myself.

  7. #7 Mike Olson
    January 28, 2010

    As for Enoch, I can only say that because I spent part of my youth as chocolate pudding seeky and still over indulge once in a while, doesn’t mean I have an eating disorder…but rather a predilection to chocolate pudding. A predilection I actively address in a variety of ways. None of which involves 12 steps, being born again or attending a life time of meetings. Admittedly, I do pray to God for a little strength now and again. I treat my “beer seeky” the same way. 12 steppers hate me at a level it is almost impossible for anyone else to understand. The only folks I know who can smile while engaging in child molestation as a form of tough love. : D

  8. #8 Silver
    January 28, 2010

    For me, much of the question comes down to: am I causing more harm by prescribing this substance? When I’m putting the patient on the couch for more hours of the day, when I’m impairing function – I’m not helping. When I see clear benefit as evidenced by function, then it’s not that hard to sort out the treatment decision. (And as to who defines “benefit?” Well, as Randy Waterhouse would say, “I do.”)
    Of course, patients lie to me. A lot. Forged prescriptions, etc.
    I’m interested by how much impulse control, etc., feed into this. As I recall, the major determinant on the SOAPP as to the risk of significant aberrancies related to controlled substances within a year: whether or not the patient smoked in the first hour after waking up. I don’t recall that questionnaire asking about coffee…

  9. #9 daedalus2u
    January 28, 2010

    A complication specific to opiate use/abuse is the recent paper showing that injured soldiers who received morphine were less likely to develop PTSD than those who did not receive morphine.

    http://content.nejm.org/cgi/content/abstract/362/2/110

    The total amount of morphine received was small, and within the standard of care for pain relief. The observed reduction in PTSD is a significant and substantial therapeutic effect.

    Many people who are opiate users and opiate abusers have experienced trauma earlier in their lives. This raises the question is their opiate seeking an attempt to self-medicate to prevent or ameliorate PTSD? If so, then treating them harshly, as criminals, will likely increase their self-medication to avoid PTSD.

  10. #10 Vicki
    January 28, 2010

    Another complication is that there are “pain clinics” whose goal is not to reduce pain, but to enable patients to handle it more stoicly: clinics where a person walks in with chronic pain and meets staff whose goal is “how can we reduce your medication?” rather than “how can we reduce your pain?” or even improving quality of life measured in any terms other than opiate intake. That’s backed by a lot of the rest of the culture: from the stuff Pal and Drugmonkey were talking about, to endless well-meaning relatives and friends who will tell people to keep a stiff upper lip, think positive thoughts, and/or that they should “be over it by now.”

    Someone may in fact be doctor-shopping, not to get prescriptions from three or four doctors at once, but to find one doctor who will take them seriously and treat their actual pain and other needs (say, balancing the way that pain makes it hard to think against the way some painkillers make it hard to think), rather than assuming either that they enjoy being stoned, or that it doesn’t matter how much pain the person is in, if they can still drive “safely,” for values of “safe” meaning that if they crash the car because the pain stops them from thinking clearly, they’ll pass a drug test.

  11. #11 OleanderTea
    January 28, 2010

    Pal, I’m impressed that you drew a parallel between your caffeine addiction and an opiate-dependent’s patient’s need. An awful lot of health-care providers view a need for opiates as a moral failing, even if you have a dx.

    I have a chronic pain condition (spinal stenosis, chronic migraine, and probable fibromyalgia). I take 3 to 4 5/325 hydrocodone daily. This allows me to function — I always have some level of pain, but if it’s below a 4, I can do stuff. I work a professional-level full-time job in IT. I have a social life. I don’t exhibit any of the behaviors that would cause a doc to have concerns. I’m a boring, compliant patient. But despite this, I’ve run into providers who want to “bargain” me down to fewer pills per day, or who suggest exercise instead of drugs. I have had to explain that stopping these meds would leave me unable to do anything but lay in bed and weep, and that what exercise I take would go by the wayside damn quick.

    It’s most troubling that physicians think that people who take opiates on a regular basis are getting stoned. Most of us aren’t. The only difference between me with meds and me without meds, is me in pain, or me just in discomfort. Oh, and my attitude sucketh muchly when I don’t have meds. It’s not because I miss the high, it’s because I HURT.

    Now, can we have a column about the woo fostered on patients with chronic conditions? A “doctor” at my pain clinic mentioned acupuncture to me as a possible treatment. *rolls eyes*

  12. #12 Christophe Thill
    January 29, 2010

    A personal comment from a non-American non-doctor: I never could get why these notions of “substance us” and “substance abuse” are so widely used in the US. To me, both “substance (ab)user” and “substance abuse disorder” put the blame on the patient, while “addiction” sounds much more like a pathology, and less like a moral fault. OK, technically there may be a difference, with people like the young British “binge drinkers” being “substance abuser” but not alcoholics. But I’m not sure people have this in mind when using the words.

    As for coffee: I had the same experience (and so did my wife) of observing its addictive effect. It feels weird when you realize it…

  13. #13 Nathan Myers
    January 29, 2010

    It’s big of you to empathize with Rush Limbaugh despite his needy, stubborn, and narcissistic character.

    Caffeine abusers also have characteristic hallucinations, but since so many other people abuse caffeine and experience the same hallucinations, they think it’s reality.

    I just quit green tea two weeks ago (it was supposed to be good for me, right?), after twelve years using, and everything in my life is improving. I smile a lot more and get along better with my kids.

  14. #14 llewelly
    January 29, 2010

    I worried that I wouldn’t get my coffee quickly enough to stave off my headache.

    For years I thought I didn’t get caffeine withdrawl headaches. Eventually, I realized that I did, but I had not noticed them because (for me) they were nothing compared to the severe headaches I regularly got throughout my childhood. (I was raised Mormon, and did not try caffeine until I was 15.)

  15. #15 E. Brown
    January 29, 2010

    I found Dr. Gabor Mate’s book ‘Realm of Hungry Ghosts’ a very thought-provoking and compassionate view of substance users.

    He works in Vancouver downtown Eastside, among the most desperate users – and he too acknowledges the addictive side of his own personality.

    http://www.drgabormate.com/ghosts.php

  16. #16 Katharine
    January 29, 2010

    I guess part of the problem is that while addiction is a legitimate medical problem, they started their addiction by using the drug. They might garner more compassion if they weren’t aware they could get addicted or thought they were using it in small enough amounts not to get addicted, in which case it was simply a mistake, but you can’t forget the fact that in many ways an addict kind of brings it upon themselves.

  17. #17 Vicki
    January 29, 2010

    Katharine–

    How many addicts do you know? And what percentage of them started off thinking that they were going to become addicted?

    Whether it’s alcohol or heroin, caffeine or nicotine or meth, people don’t start off thinking “hey, I want to be a drug addict.” They start off thinking “it feels good, and it’s just one” or “everything hurts, maybe this will help” or “I need to be awake for that meeting/to finish this term paper/to drive.”

    The percentage of users who become addicted varies from drug to drug, and context to context. I wouldn’t be surprised if you have used at least one of the addictive substances I listed above: most non-Mormon Westerners have. And lots of people drink alcohol without becoming addicted. Some drink tea or coffee or cola without becoming addicted. Some use narcotics without becoming addicted, especially if it’s for short-term pain (post-surgical and dental are relatively common). A few even manage to use nicotine without addiction.

  18. #18 Dave Munger
    January 29, 2010

    Katherine,

    Plenty of disorders are related to behavior. Do you not treat someone who was in a motorcycle accident? They could have been driving a Camry, or just stayed home. Diabetes is related to overeating, as is heart disease. Do the people with these disease not merit treatment?

    Do we give the “truly innocent” victims plusher hospital rooms and better care? Or do we strive to treat everyone equally?

  19. #19 JohnV
    January 29, 2010

    I move that all camry drivers be denied emergency care due to driving cars with a known defect!

  20. #20 DrugMonkey
    January 29, 2010

    As everyone is gearing up to jump all over Katharine let us introspect. Everyone has some little tiny bit of this approach and it is *very* hard to eradicate from our thinking. PalMD has had blogposts and at least one memorable PalCast where he talked about struggling to keep the idea that an addict is not in willful control in mind, about stamping down our inner moralizer about past behavior, etc.

    Dave Munger makes the excellent point. *Many* of our medical conditions arise because of *prior choices* on the part of the patient. Do you moralize the same way about those? No? Why not?

  21. #21 PalMD
    January 29, 2010

    Yes, in fact, people do. It’s very frustrating to me as a physician to hear colleagues and others talk about volition in a punitive way, since really, it’s our fucking job to help people get fixed.

  22. #22 becca
    January 29, 2010

    I do kind of wonder how much of the moralizing is functional- that is, I think there’s a certain class of person who moralizes dramatically to keep themselves from doing something. Of course, that’s how you end up with hypocrites too.

  23. #23 Donna B.
    January 29, 2010

    #20 – “*Many* of our medical conditions arise because of *prior choices* on the part of the patient. Do you moralize the same way about those? No? Why not?”

    Oh but far too many people do moralize the same way about other conditions — especially diabetes. So much so that I have extra pity for Type I’s who are often assumed to have “brought it on themselves” also.

  24. #24 SurgPA
    January 29, 2010

    @2: In my dealings with acute surgical post-op pain, I write prescriptions daily totalling 50-200 tabs of percocet (oxycodone/APAP) or the equivalent. My aggregate prescribing may not set records but certainly exceeds the median. I’ve never had DEA inquiries, FWIW. When I first started practice, the director of the NH Board of Pharmacy specifically told me that they don’t second-guess providers based on volume of narcotics prescribed, so long as the documentation supports the need. While there may be (unfounded) concerns about crossing the DEA, my understanding is they do NOT target or pressure providers or question their clinical judgement about treatment decisions.

  25. #25 SurgPA
    January 29, 2010

    @9 While this may be the case, I think that may be an oversimplification. PTSD is an increasingly recognize outcome of military combat and injury. I would interpret these findings as showing that early and appropriate treatment of pain associated with trauma reduces the risk of developing PTSD related to that event, rather than that some pharmacologic effect of morphine treats PTSD directly.

  26. #26 leigh
    January 30, 2010

    the moralistic bullshit some part of our society perpetuates blows my mind. how effectively do we really place the blame, when only hindsight is 20/20? while it’s particularly prevalent when it comes to illicit substances, this goes far beyond substance abuse as well. having been through some substantial expense and very hard times due to a medical condition, i have had people try to explain to me why it’s all our fault and we got what we deserved. (they stop short of “maybe you’ll think ahead next time!” as i roll up my sleeves.)

    really? why stop there? there is some blame to be passed around for my very existence and my care and feeding as a child and early adolescent. care to call up mom and dad and tell them so?

    i’m all for thinking ahead and personal responsibility- but there are limitations to such things, and people are flawed. might as well live with this last fact and quit the blame game.

  27. #27 red rabbit
    January 30, 2010

    I appreciate this post. It’s a tough line to walk: knowing when you’re adequately treating someone’s pain is difficult. Knowing when you’re getting jerked around isn’t necessarily straightforward either.

    I had a guy lie his way into the ED (chest pain, feels like an elephant sitting there, OMG and my dad died of a heart attack in his 40′s) in order to ask me for a “taper” so he could “come off the oxycontin.” I was a resident at the time and I got every addiction resource I could find. He threw it all in my face and stomped out.

    So yeah, a hard line. Oxycontin 10 mg tabs go for $50 in my community. There’s a lot of unemployemt. We’re pretty rural here, as well, but old ladies coming out of the drugstore get mugged. For me, I cannot cannot cannot be an enabler to this sort of crap.

    Unfortunately, that makes everyone, including people with legit pain issues (the majority of people, IMHO) a suspect. It’s the whole one asshole ruins it for everyone situation.

  28. #28 daedalus2u
    January 30, 2010

    SurgPA, many (probably most) cases of PTSD are not secondary to physical pain, but are rather secondary to psychological trauma. First responders to natural disasters get PTSD which is unrelated to physical pain. If physical pain is not necessary for PTSD to develop, a pain-relief mechanism is likely not relevant to preventing it.

    Morphine is a signaling molecule itself, and is generated in normal human physiology in very small quantities. There is a lot of cross-talk between opiate, catecholamine, and NO pathways. It seems perfectly plausible to me that morphine would have specific therapeutic effects in reducing PTSD.

    I suspect that the availability of heroin in the Vietnam era may have reduced the incidence of PTSD in Vietnam era vets over what is now being seen in Iraq.

  29. #29 leigh
    January 30, 2010

    daedalus @28: the study you cite talks about a preventive use for morphine, not a treatment use in PTSD that has already developed. you’re making massive generalizations here that i don’t see a base for. physical pain associated with psych trauma may increase the risk of PTSD, for instance. the fact that psych trauma without physical pain can also lead to PTSD does not rule out the role of pain in the process. also, consider the very different combat environments of the vietnam era vs now. we have much higher survival of traumatic combat events thanks to technological advances, but more survivors of traumatic events itself could be a major factor in the increased PTSD of this generation’s veterans.

  30. #30 Kristen
    January 31, 2010

    I am so glad you wrote this, just wanted to add my two cents:

    There are so many complexities to this issue. My mother is dependent on opiates (I am finding out, since I was little). But how she came to be dependent is very unique.

    My father compressed three vertebrae in 1991, and also crushed his left hand (heavy equipment mechanic, happened to be left-handed). He has been in incredible pain ever since, more or less as long as I can remember.

    Through all the surgeries and physical therapy, he would always take his pain meds only when he goes to bed. He is afraid of becoming dependent so much that he is willing to deal with any amount of pain. He became very abusive to my mother and us around the same time, she coped by taking his medication.

    I am not condoning drug-dependence, I hate that my mother does this, I don’t want her around my kids and I feel like her addiction has messed up her life. But I think the intricacies of individual circumstances gets lost in so many debates of this kind.

    Sorry for the rambling.

  31. #31 daedalus2u
    January 31, 2010

    Leigh, you are correct. The study I cited was about morphine use during acute trauma decreasing the incidence of PTSD later, not about treating already existing PTSD.

    However, PTSD is an ongoing state. There must be physiological mechanisms that maintain the state of PTSD. Presumably there is some correspondence between the physiology that causes PTSD and the physiology that maintains it. PTSD is a state which has resulted from neuronal remodeling (neuronal remodeling is what produces all brain states). Neuronal remodeling in a high stress state can lead to PTSD, whether that high stress is from pain, anxiety, fear of death, abuse, or what ever.

    It is probably much easier to prevent PTSD than to reverse it once it has happened.

    I have PTSD from childhood psychological abuse, so I am not unfamiliar with it, and I have also read a lot about it. I see PTSD as the “normal” response to being in a chronic state of extreme stress. If you are living in a war-zone, it is a “feature” to be hyper-vigilant, unable to sleep, anxious, quick to anger and quick to resort to indiscriminate violence. In a war-zone those things might just save your life. Maybe not so much now when it is bombs and bullets that kill, but it would have during evolutionary time when it was death by hand-to-hand combat killed people.

    I think the military simply doesn’t want to acknowledge that PTSD can happen to anyone, and that it is a normal and foreseeable consequence of being in a war, and an injury that should be acknowledge and treated as best it can be treated. That is why they play games and give soldiers the “choice”, admit that you have PTSD and be treated in theater for 6+ months, or sign a piece of paper saying you don’t have PTSD and be discharged immediately. The military doesn’t care. The military contractors don’t care, the politicians don’t care, the military industrial complex doesn’t care. If they did care, they wouldn’t do things the way they are doing them.

  32. #32 SurgPA
    January 31, 2010

    daedalus2u,

    I’m not arguing that physical pain alone is the major contributor to PTSD. However, as you said, “stress may be from pain, anxiety, fear of death, abuse, or what ever.” If, as you say, pain may contribue to stress, and stress causes PTSD, wouldn’t it follow that relieving that pain by any method (with or without morhpine) reduces stress and may prevent subsequent PTSD? My original point was that you are drawing conclusions beyond what the study demonstrates. It was a retrospective study looking only (apparently) at morphine vs non-morphine use in acute trauma. Did the non-morphine cohort get an alternative analgesic? If the controls all received hydromorphone/fentanyl/other-narcotic *with equal analgesic effect,* I might be more inclined to agree with you, but the authors don’t say. For now, the only conclusion I can draw is that the morphine cohort developed less PTSD. Maybe something specific to morphine, maybe just the effect of adequate analgesia. I certainly know from personal trauma (odd assortment of fractures, dislocations and lacerations over the years) as well as from treating patients with similar injuries that stress/anxiety/fear levels (heart rate, blood pressure, plus subjective measures) decrease almost as soon as pain is relieved.

    While we’re at it, your second paragraph in #9 is an even bigger leap (think Evel Kneivel and Snake River Canyon). The study looked at early intervention with morphine to prevent PTSD. You are now extrapolating from a premature conclusion to a dubious hypothesis that late intervention with self-prescribed morphine is a subconscious effort to prevent PTSD that was probably already set in motion in the remote past.

  33. #33 daedalus2u
    February 1, 2010

    Morphine signaling is considerably more complex than pain regulation.

    http://www.spandidos-publications.com/ijmm/article.jsp?article_id=ijmm_20_6_837

    It would not be surprising if morphine had broader regulatory roles than just pain. If it couples to the major stress pathways it could have major effects on the outcome of stress independent of pain.

    There is other literature on the use of morphine preventing PTSD, in children with severe burns where they do talk about stress pathways that morphine couples to other than pain.

    http://www.ncbi.nlm.nih.gov/pubmed/11501691?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=37

    I agree it is premature to prescribe morphine to prevent or treat PTSD. It would be useful to see if morphine does treat or prevent PTSD. The amounts needed might be much smaller than what is needed for pain relief. The NEJM article didn’t show a dose-response relationship. I suspect it will be very difficult to get approval and funding for such research because of the stigma associated with use of opiates.

    My perspective of PTSD is that it is a normal physiological state, a normal state brought about by extreme stress. That state has hysteresis because any state that is worth remodeling the brain to achieve is worth staying in until it is no longer necessary. Whether to be in a state of PTSD or not in a state of PTSD is a “decision” that physiology makes, and then invokes physiology to either produce the PTSD state or to end the PTSD state. These are signaling events. Signaling events that trigger the physiology that causes the remodeling in the brain and in the endocrine system that produces the PTSD phenotype.

    It takes neuronal remodeling to achieve a state of PTSD, it will take neuronal remodeling to get out of a state of PTSD. What conditions someone has to be subjected to in order to achieve the remodeling that ends a state of PTSD is unknown, but it is likely to be the opposite of the conditions that brought about the PTSD in the first place.

    My main focus is on nitric oxide. Morphine does couple to NO pathways through the opiate receptors which cause the release of NO. I suspect that some of the effects of morphine on reducing PTSD are due to pathways involving NO. Supplying more NO is likely to be considerably less objectionable than supplying morphine. The potential for abuse of NO is simply not present. Neuronal remodeling is regulated a great deal by NO. The neuronal remodeling necessary to reduce a state of PTSD is likely to be affected by NO also, and likely to be increased by increased NO levels (a high NO state being the opposite of a high stress state).