20181106

Suffering and Death: Law and ethics presentation.

This was written for my presentation in my Law and Ethics class, delivered June 13, 2018.

Suffering and Death

Suffering is overrated. Mother Teresa saw beauty in suffering, (1, p. 11). She has likened it to a kiss from Jesus, (2). Likewise, I think that the general population holds an implicit view that is similar to this.

Death, on the other hand, is vastly underrated. Death is one of the most efficient remedies to suffering. Death is only problematic insofar as it generates suffering for those who are still alive. However, avoidance of death on these grounds is often only delaying the inevitable. Furthermore, it seems wrong to make someone suffer for ones own benefit. Insofar as this principle is agreed upon, we should strive to offer death to those in need.

Washington state does have one measly Death With Dignity Act. It is quite pathetic in scope. The act only allows death for those with 6 months or less to live, (3). Last year, lethal medication was dispensed to scant 200 patients, (3). Not all of them have taken the medication, but I find that to be ethically irrelevant. I find the fact that a patient must ask for the right to a graceful exit to be morally disgusting.

Blackstone's formulation is the principle that it is better to let ten criminals free than convict one innocent person. Our courts operate on this principle. The phrase "innocent until proven guilty" is one manifestation of this commitment. I, for one, agree with this principle as a matter of law. Naturally, in this analogy, life is the prison, and death is freedom. It is better to kill ten people than to let one suffer unwillingly. Likewise, it is better to prevent births when the baby is likely to suffer.

Schizophrenia is a genetic psychotic disorder. More specifically, it may be a genetic sleep disorder, (4). The rate of attempted suicide in schizophrenics is extremely high. The lower-bound estimate for suicide attempts among schizophrenics is 20%, (5). This 5:1 ratio fails to conform to the Blackstone ratio of 10:1. As such, this seems to be one of the more obvious cases where births should be prevented. Even sadder, many of those attempting suicide will never succeed. At the very least, schizophrenics should be given suicide drugs at the time of diagnosis.

There is a nonprofit organization called the Final Exit Network; named after the book "Final Exit." They offer information on how to commit suicide. By the bounds of law, they cannot directly assist in the suicide, but they can provide company and support. I'd certainly like to volunteer with them. However, even they are insufficient. They run each case by a team of doctors; a practice I find despicable, as it again enters the territory of asking permission. Nevertheless, it is not quite clear how much of their practice is designed to keep themselves safe from the law.

Antinatalists argue that it is unethical to have children. From a deontological perspective, their case is strong. Reproduction is a gamble with someone else's life. Nevertheless, there are other ways around this. In any case, as a utilitarian I am forced to explore alternative solutions to ending unwilling suffering.

People often ascribe value to suffering where there is none. People with pain asymbolia lack negative associations with painful stimuli. In effect, they are able to experience the sensation of pain without the associated suffering. Of course, this flies against the very notion of "pain," and will likely require a new word in the dictionary. In any case, these people can be trained to avoid damaging situations without the need to suffer. As such, suffering seems unnecessary in this regard.

Some people, such as myself, might assume that suffering is necessary for empathy. It turns out, however, that this is just an assumption without much empirical backing. People with congenital analgesia are born with a complete inability to feel physical pain. Unlike those with pain asymbolia, they'd have no way of knowing if their finger was broken without looking. Nevertheless, these people seem to have no deficit in empathizing with those in physical pain, (6).

However, humans are not the only, nor even the primary subjects to which these concerns apply. One obvious example is research animals. If death is ultimately not a big deal, can it be justified to torture animals for the sake of preventing human death?

From a deontological, rights based perspective, food animals deserve immediate extermination. The suffering imposed on farms is beyond reasonable comprehension of the human mind. We have bred entire species predicated on disease causing selections. Chickens, for example, can grow too large before there bones are developed and become crippled with arthritis.

Indeed, the scope of concern for non-human animals extends much further than that. The modern philosopher Brian Tomasik argues that Wild Animal Suffering (WAS) is unacceptable. He argues that suffering outweighs happiness in nature, and that we should reduce biomass to eliminate foodstuffs that fuel suffering. Brian Tomasik is a negative utilitarian, meaning that he only cares about reducing suffering. His arguments are so compelling that I, as a classical utilitarian, can't help but to agree. From the perspective of a negative utilitarian, total destruction of earth is an ideal solution to WAS. Even to a classical utilitarian, I'd argue that this is a reasonable solution if one doesn't believe that society will remedy the situation one day.

There is another solution that I would be remiss were I to fail to mention. The modern philosopher David Pearce argues that we should use biotechnology to abolish suffering throughout the living world. In humans, the first step is using eugenic technologies to weed out unfavorable genotypes. The aim is to upregulate the hedonic set point, such that the spectrum of experience lies well above hedonic zero. Being set on fire would merely be less pleasant than a back massage, rather than horrific. The potential of preimplantation genetic screening and genetic engineering is boundless.

Eugenics has historically received a bad name. Largely, this is a function of the utilization of negative eugenics. That is to say, we would forcefully prevent people from breeding. In contrast, positive eugenics promotes the advancement of desired genes. Furthermore, the interest of those being born is oft not considered. Selecting against depression and anxiety are moral imperatives. Whether it is ethical to sterilize depressives, schizophrenics, and the anxious is a more sensitive issue. Given my Ashkenazi ancestry, and the rate of CNS diseases among Ashkenazi Jews, it seems that I should not be allowed to procreate via natural means. What is clear is that people must be offered the chance to use biotechnology to eliminate these risks in their offspring.

In summary, the utility of death needs to be taken more seriously. Furthermore, suffering is a much neglected issue. It is unethical to force life on the suffering. Even to allow the suffering to live is ethically questionable.

References

1. Hitchens, C. (1995). The missionary position: Mother Teresa in theory and practice. New York: Verso
2. WHATEVER YOU DID UNTO ONE OF THE LEAST, YOU DID UNTO ME. (n.d.). Retrieved June 13, 2018, from http://www.ewtn.com/New_library/breakfast.htm
3. Center for Health Statistics. (2018) Death With Dignity Act Report. Retrieved June 13, 2018, from https://www.doh.wa.gov/Portals/1/Documents/Pubs/422-109-DeathWithDignityAct2017.pdf
4. D’Agostino, A., Castelnovo, A., Cavallotti, S., Casetta, C., Marcatili, M., Gambini, O., … Sarasso, S. (2018). Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives. NPJ Schizophrenia, 4, 2. http://doi.org/10.1038/s41537-018-0045-9
5. Verma, D., Srivastava, M. K., Singh, S. K., Bhatia, T., & Deshpande, S. N. (2016). Lifetime suicide intent, executive function and insight in schizophrenia and schizoaffective disorders. Schizophrenia Research, 178(1-3), 12–16. http://doi.org/10.1016/j.schres.2016.08.009
6. Danziger N, Faillenot I, Peyron R. Can We Share a Pain We Never Felt? Neural Correlates of Empathy in Patients with Congenital Insensitivity to Pain. Neuron 61: 203–212, 2009.

20180829

The case for high dose hydroxyzine for sleep.

"
/SIGNS AND SYMPTOMS/ In general, overdosage of hydroxyzine may be expected to produce effects that are extensions of common adverse reactions; excessive sedation has been the principal effect reported. Hypotension, although rare, may also occur.[American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2630] **PEER REVIEWED**", (1).

Given this information, it seems likely that very high doses of hydroxyzine would be appropriate for insomnia. The primary side effect of hydroxyzine is one of therapeutic value: namely sedation.

At 400 mg per day, hydroxyzine has been found effective for anxiety, (2). Patient drop out rate due to side effects was high; given that sedation was the chief side effect, this is evidence for its effectiveness for insomnia. However, some subjects reported mild, as opposed to marked, sedation. Therefore, it's plausible that higher doses could be required by some people. Nevertheless, if 400 mg is administered in a single dose at night, then peak values and thus effectiveness should be greater than 400 mg throughout the day.

Tolerance to the sedating effects of antihistamines develops rapidly. Complete tolerance to sedation from diphenhydramine (benadryl) occurs on the fourth day of twice daily administration, (3). Three times daily administration results in complete tolerance on the third day, (4). However, antihistamines increase slow wave sleep (SWS, AKA deep sleep) in mice, rats, and guinea pigs, (5,6). Expectedly, this enhanced sleep results in rebound wakefulness upon withdrawal, (6). Therefore, it is not clear whether tolerance to antihistamine sedation per se develops rapidly, or if apparent tolerance is simply a sleep surplus. In any case, this insures that daytime sedation is unlikely after a few days of use for insomnia.

Regardless, hydroxyzine is also a 5-HT2A antagonist. In addition to improving sleep architecture, 5-HT2A antagonists are appealing because they lack tolerance, generally displaying reverse tolerance instead, (7,8). That is to say, one becomes more sensitive to the effects of the drug with repeated use, as contrasted to drugs losing their effectiveness in the case of normal drug tolerance.

Most antihistamines have anticholinergic side effects. While low acetylcholine is important during SWS, high levels are important for REM sleep, (9). For this reason, diphenhydramine reduces REM sleep, while less anticholinergic antihistamines (i.e. ketotifen) do not, (10). Hydroxyzine has comparatively insignificant anticholinergic effects, (11).

Hydroxyzine in doses up to 100 mg is able to improve sleep in PTSD, (12). However, 1 mg/kg (or about 70 mg for a normal adult) hydroxyzine to children is not as efficacious as 50 mg/kg chloral hydrate, (13). Nevertheless, melatonin plus 1.5 mg/kg hydroxyzine is able to reduce the need to take chloral hydrate from 37.1% to 6.7% in children undergoing EEG analysis, (14). Anecdotes had interested me in the 200-300 mg dose range. The study referenced above (2) makes me think that 400 mg may be adequate for most people, but not for everyone. I had been taking 150 mg hydroxyzine nightly for several weeks (Blog post) and have found it somewhat helpful, yet generally inadequate. I would like to try 300-400 mg.

References

(1) https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+68-88-2

(2) Rickels, K., Gordon, P. E., Zamostien, B. B., Case, W., Hutchison, J., & Chung, H. (1970). Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: A collaborative controlled study. Comprehensive psychiatry, 11(5), 457-474. Abstract, Sci-hub

(3) Richardson, G. S., Roehrs, T. A., Rosenthal, L., Koshorek, G., & Roth, T. (2002). Tolerance to daytime sedative effects of H1 antihistamines. Journal of clinical psychopharmacology, 22(5), 511-515.

(4) Schweitzer, P. K., Muehlbach, M. J., & Welsh, J. K. (1994). Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. Journal of allergy and clinical immunology, 94(4), 716-724.

(5) Lin, J. S., Sergeeva, O. A., & Haas, H. L. (2011). Histamine H3 receptors and sleep-wake regulation. Journal of Pharmacology and Experimental Therapeutics, 336(1), 17-23.

(6) Ikeda-Sagara, M., Ozaki, T., Shahid, M., Morioka, E., Wada, K., Honda, K., … Ikeda, M. (2012). Induction of prolonged, continuous slow-wave sleep by blocking cerebral H1 histamine receptors in rats. British Journal of Pharmacology, 165(1), 167–182. http://doi.org/10.1111/j.1476-5381.2011.01547.x

(7) Vanover, K. E., & Davis, R. E. (2010). Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nature and Science of Sleep, 2, 139–150.

(8) Yadav, P. N., Kroeze, W. K., Farrell, M. S., & Roth, B. L. (2011). Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo. The Journal of Pharmacology and Experimental Therapeutics, 339(1), 99–105.

(9) Gais, S., & Born, J. (2004). Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proceedings of the National Academy of Sciences, 101(7), 2140-2144.

(10) Katayose, Y., Aritake, S., Kitamura, S., Enomoto, M., Hida, A., Takahashi, K., & Mishima, K. (2012). Carryover effect on next‐day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Human Psychopharmacology: Clinical and Experimental, 27(4), 428-436. Sci-hub

(11) Kubo, N., SHIRAKAWA, O., KUNO, T., & TANAKA, C. (1987). Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay. The Japanese Journal of Pharmacology, 43(3), 277-282.

(12) Ahmadpanah, M., Sabzeiee, P., Hosseini, S. M., Torabian, S., Haghighi, M., Jahangard, L., ... & Brand, S. (2014). Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. Neuropsychobiology, 69(4), 235-242.

(13) Sezer, T., & Alehan, F. (2013). Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording. International Journal of Neuroscience, 123(10), 719-723.

(14) Dirani, M., Nasreddine, W., Melhem, J., Arabi, M., & Beydoun, A. (2017). Efficacy of the sequential administration of melatonin, hydroxyzine, and chloral hydrate for recording sleep EEGs in children. Clinical EEG and neuroscience, 48(1), 41-47.

20180627

Glycerin Hygroscopy Values: Results From My Experiments. AKA Putting On My Nerd Pants.

This is a short deviation from my usual writings. I'm not applying my usual rigor with citations because I'm mostly citing facts that can easily be looked up.

Preamble

I use vegetable glycerin (AKA glycerol) to dampen supplements so that they compact more tightly. This allows me to fit more in a smaller space, and also allows supplements to sink to the bottom of the stomach. For example, spinach powder is relatively light and fluffy. I'd estimate that I can fit 30% more spinach into a capsule if I add glycerin. Additionally, when glycerin is added it doesn't bounce back when compacted, therefore making it easier for me to fill pills to maximum capacity.

The Conundrum

"Why glycerin?", you may ask.Using water would provide a breeding ground for mold and bacteria. Thus, I use glycerin precisely because it is not water. High levels of glycerin can be used as a food additive to preserve food, much like sugar or salt. It lowers water activity, limiting the ability of microbes to grow.

Additionally, there is one other reason I'm using glycerin. Initially, I had tested both glycerin and propylene glycol, filling a vegetable cellulose capsule with each respectively. The capsule filled with propylene glycol dissolved, while the capsule filled with glycerin did not. Thus, I settled on vegetable glycerin.

However, I began to notice something strange. Over time, capsules to which I had added glycerin began to become stretched, and the outside of the capsule became wet. Glycerin is hygroscopic, meaning that it can absorb water from the air. As such, the fluid volume increased, expanding the capsule and overflowing into the container.

Therefore, I ran a second experiment. I combined glycerin with various amounts of water, and put it into capsules. I found that large amounts of water could be added without dissolving the capsule. The cellulose capsules could withstand at least 50% water, or 1 to 1 glycerin to water by weight. However, the larger quantities of water did warp the capsules slightly. Nevertheless, I ended up using a 1 to 1 ratio

Refinement
But the story doesn't end there. Sure, 50% water worked, but was it optimal? I wanted to get the water activity as low as possible. I always make at least a month's supply of pills, usually 3 months' worth. Thus, the more certainty that the pills will preserve, the better. So I ran a third experiment. I put 100 grams of glycerin into an open container, labeled it, set it at the back of my desk, and forgot about it. I weighed it every so often, when the fancy struck. Months later, I put it on the scale; it weighed exactly 40 grams more than the starting weight.

Thus, my new mixture of 40 parts water per 100 parts glycerin was born. However, I still needed to confirm that this was the maximum water holding capacity of glycerin. I filled a container with 50 parts water to 100 parts glycerin to see if it would continue to increase or not. As it turns out, it decreased in weight, suggesting that water evaporated.

Final Results

OK. So we have the hygroscopic capacity of glycerin. We're reasonably confident that pills will preserve. What's missing? Details. For example, how does humidity affect the hygroscopicity of glycerin? How long does it take for glycerin to absorb water? What about alternative units, and using volume instead of weight? I've taken care of that. In a final experiment, I set up a small amount of glycerin and meticulously tracked its weight over time. I converted it to various units. Note that percent is expressed as a fraction. I also looked up humidity at time of measurement, but it didn't fit neatly on the graph. You're welcome to check out the that data in the original spreadsheet. As you can see, I could lower the water content of my recipe from 40 parts per 100 to 38 or so (as seen in red: the weight ratio of water to glycerin)

20170808

Pre-paper report on the basics of diabetes and insulin resistance.

I just wrote a youtube comment about diabetes and realized that I haven't yet made a compilation on it. Here, then, is a taste. Diabetes is caused by fatty molecules that infiltrate muscle and other cells and interfere with the function of insulin. In particular, ceramides, a fatty molecule, is the prime culprit for insulin resistance. However, not all fats are equally suspect. Long-chain saturated fatty acids (LCSFAs) induce acute (rapid) postprandial (after meal) insulin resistance. Long term, the claim holds true, but studies need good controls since exercise and weight loss can, at least partially, burn off the problematic molecules. I will have to discuss the pathogenesis of diabetes at a later date. For now, here are some controlled trials.

Type 1 diabetics in a crossover design, when given identical carbohydrates and protein content, saturated fat results in needing to inject more insulin AND having greater glucose levels. This is strong clinical evidence that not only supports the link between saturated fat and diabetes, but demonstrates that a single meal containing saturated fat results in postprandial insulin resistance. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609492/
Increased insulin was also found in healthy post-menopausal women, but the insulin spike was dramatic enough to prevent excessive hyperglycemia. Control groups were unsaturated fat. https://www.ncbi.nlm.nih.gov/pubmed/12493085
The same was found for non-insulin-dependent diabetes. Butter increased insulin spike, but olive oil did not. https://www.ncbi.nlm.nih.gov/pubmed/8561067

Likewise, a meta analysis of randomized controlled trials found that replacing animal protein with plant protein improved glycemic control in diabetics. http://www.mdpi.com/20726643/7/12/5509/htm

I have mechanistic and other data available. My research notes on saturated fat can be found here (does not include all research I've done, but a good chunk of it).

20170802

The case for a new sleep parameter; parasympathetic tone. (ME/CFS, POTS, and HRV)

Introduction

Classic sleep parameters involve several sleep stages. These stages are identifiable via their unique brainwave patterns. Namely, rapid eye movement sleep (REM sleep), light sleep (stage 1 and 2 sleep), and deep sleep (stage 3, previously divided into stages 3 and 4). Stages 1-3 are also grouped as non-REM sleep (NREM sleep). The time spent in, and distribution of, each sleep type during the night is known as sleep architecture (not elaborated in this paper). Sleep architecture is the classical measure of objective sleep parameters.

For the purposes of this paper, I will be writing mostly about deep sleep (stage 3). Deep sleep, also known as slow wave sleep (SWS), is characterized by slow, delta waves. These are long, lazy waves that are a result of a large number of neurons firing synchronously. Additionally, the brains waste clearance system, the glymphatic system, is active during deep sleep.

Discussion

Each sleep stage has been linked to specific cognitive functions. What's more, manipulating brainwaves can alter cognitive functions. For example, using a polysomnographic brain-computer interface to precisely time audio pulses to enhance slow wave amplitude can enhance memory consolidation compared to both no audio and mistimed audio, (1).

However, there is a sleep parameter that I think has been largely neglected; autonomic tone. The autonomic nervous system (ANS) consists of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). While the SNS is characterized by "fight or flight" functions, the PSNS is characterized by "rest and digest" functions. By extension, it is reasonable to predict that the PSNS plays a role in sleep. Likewise, it would be expected that SNS activation would disrupt sleep.

Indeed, incorporating a measure of autonomic tone (namely, heart rate variability) can radically increase the predictive power of memory consolidation during sleep compared to brainwaves alone, (2). Heart rate variability (HRV) is a measure of change in heart rate from beat to beat. The heart rate changes rhythmically through the breathing cycle; increasing during inhalation and decreasing during exhalation. Since the heart rate is controlled by the ANS, heart rate and heart electrical parameters can be used as a measure of SNS and PSNS activation. High HRV indicates high parasympathetic tone.

One disease that is associated with autonomic dysfunction and has an obvious connection to sleep is chronic fatigue syndrome (CFS). CFS is characterized by extreme fatigue, malaise (particularly post-exertional malaise), and unrefreshing sleep. What's more, CFS is associated with pain such as sore throat, headaches, and fibromyalgia (FM; translates to muscle pain). In fact, CFS is also called myalgic encephalitis (ME), which translates to muscle pain (myalgic) and brain inflammation (encephalitis). The condition is often referred to as "ME/CFS". All of these symptoms, as I will argue, can be explained by disrupted sleep. Specifically, disrupted deep sleep.

Sustained SWS disruption results in pain. Experimentally, disrupting SWS causes muscle pain, (3,4). Likewise, sensitivity to pain in general is increased, (5-8). Recovery sleep restores pain sensitivity, (5,9). Therefore, we would expect to find disrupted sleep in ME/CFS. Indeed, that is exactly what we find, (6,10-12). In particular, we find that alpha waves intrude into NREM sleep, including the delta waves of SWS, (6,10,11,13). However, this feature is not exclusive to ME/CFS. For example, it can also be found in rheumatoid arthritis and depression, (6,14,15).

Even though its possible to identify ME/CFS from brainwave patterns, it is, as I will argue, a downstream symptom of autonomic tone. ME/CFS patients can present with other sleep disorders in absence of alpha intrusions, (6,16-18). Thus, alpha intrusions are neither sufficient nor necessary for ME/CFS. Alpha intrusions can, nevertheless, be a marker. However, reduced HRV is a much better predictor, (18-22). This cardiac parameter indicates a decrease in parasympathetic tone and an increase in sympathetic tone.

The cause of reduced HRV in ME/CFS appears to be reduced blood volume and/or small heart syndrome, (23-26). In either case, the result is the same; reduced stroke volume (blood pumped per heartbeat) and reduced cardiac index (liters per minute). This necessitates an increase in sympathetic tone and decrease in parasympathetic tone in order to maintain blood pressure. Indeed, the absence of hypertension (high blood pressure) despite the autonomic shift in ME/CFS can, in and of itself, be used as an argument for reduced stroke volume in CFS. Stroke volume correlates with fatigue even in healthy subjects, (27).

This results in several interesting downstream markers. For example, reduced blood pressure variability, elevated diastolic blood pressure during sleep, and hypotension during a tilt-table test, (20,28,29). Additionally, ME/CFS is associated with either orthostatic (standing upright) hypotension, or orthostatic tachycardia (accelerated heart rate), (30-32). Postural orthostatic tachycardia syndrome (POTS) is a condition where there is an excessive increase in heart rate while standing up. This is the result of reduced preload and stroke volume because blood that is attempting to return to the heart is being pulled to the lower part of the body by gravity. Naturally, the reason for the increased heart rate is for maintaining blood pressure, and failure to increase heart rate results in hypotension, (29,30). Reduced pulse pressure can also be observed, (31).

Conclusions

ME/CFS is a sleep disorder that ultimately appears to be a result of a shift towards increased sympathetic tone and decreased parasympathetic tone. This, in turn,  is the result of reduced stroke volume. Note, however, that the sympathetic nervous system increases stroke volume, so the specific claim is that ME/CFS patients have reduced stroke volume proportional to their sympathetic tone, not necessarily reduced absolute stroke volume (though absolute reductions might also be expected).

Convergent evidence indicates that autonomic activity is important in sleep. Autonomic activity is both an independent sleep parameter and a cause of disrupted sleep architecture/microarchitecture. In particular, HRV is a good independent marker of sleep quality.

Additional notes

Brain inflammation in ME/CFS is easily explained by impairment of sleep's waste clearance. However, given how recently the glymphatic system was discovered, I'm not aware of any research directly linking them. Nevertheless, anesthetics that produce slow waves also activate the glymphatic system, (33). Therefore, it is reasonable to surmise that alpha intrusions would impair glymphatic function and lead to downstream inflammation.

At least one analysis attempts to refute the relevance of alpha intrusions into delta waves, (34). It said that there is often confusion between tonic and phasic alpha frequency activity patterns. However, the remainder of their expertise is invalidated when they claim that the brain is the only organ that is affected by sleep. Given immense amounts of research, this is an absurd claim. In fact, one would be hard pressed to find an organ that isn't affected by sleep, especially if we count indirect factors. Insulin resistance, for example, is an experimentally inducible result of sleep deprivation that directly impacts muscle.

I discluded two interventional studies that are less consistent with SWS deprivation increasing pain, (35,36). One suggests an associated between SWS and sleep duration, so the results may be due to recovery sleep, (35). The other did suggest an insignificant lowered pain thresholds in the morning in the experimental group, (36). Given the short duration of these studies, the outcome will be dramatically affected by the state of the subjects coming into the study (e.g. sleep debt). Since false negatives are easier than false positives in statistics (via relatively poor controls and/or high population variability), these are not sufficient evidence against the claim.

I'm now on Patreon. If one benefits from my efforts, one might consider donating. :)
https://www.patreon.com/user?u=7170541

References

(1) Bellesi, M., Riedner, B. A., Garcia-Molina, G. N., Cirelli, C., & Tononi, G. (2014). Enhancement of sleep slow waves: underlying mechanisms and practical consequences. Frontiers in Systems Neuroscience, 8, 208. http://doi.org/10.3389/fnsys.2014.00208

(2) Whitehurst, L. N., Cellini, N., McDevitt, E. A., Duggan, K. A., & Mednick, S. C. (2016). Autonomic activity during sleep predicts memory consolidation in humans. Proceedings of the National Academy of Sciences of the United States of America, 113(26), 7272–7277. http://doi.org/10.1073/pnas.1518202113

(3) Moldofsky, H., & Scarisbrick, P. (1976). Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosomatic medicine, 38(1), 35-44. https://www.ncbi.nlm.nih.gov/pubmed/176677

(4) Lentz, M. J., Landis, C. A., Rothermel, J., & Shaver, J. L. (1999). Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. The Journal of rheumatology, 26(7), 1586-1592.

(5) Onen, S. H., Alloui, A., Gross, A., Eschallier, A., & Dubray, C. (2001). The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. Journal of sleep research, 10(1), 35-42.

(6) Drewes, A. M. (1999). Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology, 38(11), 1035-1038. https://doi.org/10.1093/rheumatology/38.11.1035

(7) Irwin, M. R., Olmstead, R., Carrillo, C., Sadeghi, N., FitzGerald, J. D., Ranganath, V. K., & Nicassio, P. M. (2012). Sleep Loss Exacerbates Fatigue, Depression, and Pain in Rheumatoid Arthritis. Sleep, 35(4), 537–543. http://doi.org/10.5665/sleep.1742

(8) Finan, P. H., Goodin, B. R., & Smith, M. T. (2013). The association of sleep and pain: An update and a path forward. The Journal of Pain : Official Journal of the American Pain Society, 14(12), 1539–1552. http://doi.org/10.1016/j.jpain.2013.08.007

(9) Faraut, B., Léger, D., Medkour, T., Dubois, A., Bayon, V., Chennaoui, M., & Perrot, S. (2015). Napping Reverses Increased Pain Sensitivity Due to Sleep Restriction. PLoS ONE, 10(2), e0117425. http://doi.org/10.1371/journal.pone.0117425

(10) Moldofsky, H., & Lue, F. A. (1980). The relationship of alpha and delta EEG frequencies to pain and mood in ‘fibrositis’ patients treated with chlorpromazine and L-tryptophan. Electroencephalography and clinical neurophysiology, 50(1), 71-80.

(11) Branco, J., Atalaia, A., & Paiva, T. (1994). Sleep cycles and alpha-delta sleep in fibromyalgia syndrome. The Journal of rheumatology, 21(6), 1113-1117.

(12) Keskindag, B., & Karaaziz, M. (2017). The association between pain and sleep in fibromyalgia. Saudi Medical Journal, 38(5), 465–475. http://doi.org/10.15537/smj.2017.5.17864

(13) Perlis, M. L., Giles, D. E., Bootzin, R. R., Dikman, Z. V., Fleming, G. M., Drummond, S. P., & Rose, M. W. (1997). Alpha sleep and information processing, perception of sleep, pain, and arousability in fibromyalgia. International Journal of Neuroscience, 89(3-4), 265-280.

(14) Drewes, A. M., Svendsen, L., Taagholt, S. J., Bjerregård, K., Nielsen, K. D., & Hansen, B. (1998). Sleep in rheumatoid arthritis: a comparison with healthy subjects and studies of sleep/wake interactions. British journal of rheumatology, 37(1), 71-81. https://doi.org/10.1093/rheumatology/37.1.71

(15) Jaimchariyatam, N., Rodriguez, C. L., & Budur, K. (2011). Prevalence and Correlates of Alpha-Delta Sleep in Major Depressive Disorders. Innovations in Clinical Neuroscience, 8(7), 35–49.

(16) Manu, P., Lane, T. J., Matthews, D. A., Castriotta, R. J., Watson, R. K., & Abeles, M. (1994). Alpha-delta sleep in patients with a chief complaint of chronic fatigue. Southern medical journal, 87(4), 465-470.

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20170730

My first week on hydroxyzine.

All claims are for a nightly dose of 150 mg hydroxyzine. Melatonin (rapid release) was taken on all nights at the same time as hydroxyzine, generally at my usual melatonin dose of 150 mcg. Two nights I took 300 mcg melatonin, but I was more tired those days (possibly unrelated), so I discontinued. I will see if timed release 300 mcg melatonin tablets work better.

Objective and/or relatively falsifiable claims.
  • I've had no headaches since starting hydroxyzine, whereas I normally experience regular headaches. Insufficient data to definitively claim that hydroxyzine is the causal factor.
  • Sleep onset latency is reduced to less than 45 minutes (usually after waiting 1 hour for hydroxyzine levels to rise, making sleep onset less than 1 hour and 45 minutes post administration).
  • Earlier sleep onset is achievable. Early sleep onset usually results in early awakenings. Its possible that this issue could dissipate with time on a stable schedule.
  • Photophobia is reduced/eliminated. Insufficient data to make a proper analysis.

Subjective claims.
  • Sleep urge at peak concentrations (~2 hours) is insufficient to desire sleep.
  • Grogginess is reduced dramatically.
  • Tiredness is reduced between 2 to 10 times, depending on reference point.
  • Tiredness is extremely stable in comparison to previously, yielding very little deviation within a day.
  • Tiredness is inversely correlated with sleep quality, compared to a previously paradoxical and unstable relationship. Presumably, this may be due to a shift from a compensatory stress response to more conventional wake promoting mechanisms.
  • Inter-day subjective variable heterogeneity is reduced dramatically. There is much more homogeneity for sleep time, sleep duration sleep quality, alertness, and energy.

Preferences and wants.
I would like to continue taking hydroxyzine. However, I would like to try an increased dose. The reasons are severalfold. I would like to see if larger doses can induce sleep urge. I would also like to have the option of earlier sleep onset without worry of early awakenings. I hope that more stable and/or enhanced sleep can improve functioning and subjective states. Lastly, I would like an antihistamine tolerance to drug metabolism ratio suitable for sustained vigilance (a theoretical benefit, not necessarily accurate).

UPDATE:
My second week on hydroxyzine (still 150 mg) has not been as successful as the first week in terms of sleep latency and sleep schedule. However, I seemed to be even less sleepy than last week. In fact, I think it was the fact that I was less sleepy that was giving me trouble sleeping. (Edit: in retrospect, I don't think it was sleep debt since I don't recall it working better after bad sleep. I think it's more likely tolerance to the antihistaminergic effects, which I was expecting, prepared for, and even counting on. I haven't quite nailed the time frame of tolerance, though given rapid tolerance to sedation from diphenhydramine/benadryl (2), I would expect to reach peak tolerance within a weak or two) Nevertheless, several differences between the two weeks need to be considered before drawing concrete conclusions. The first week I was visiting family, was woken up by their bustling (providing sleep debt to help me sleep), ate differently, and did different activities. Furthermore, this second week I tried incorporating methylxanthine (caffeine and theobromine) tolerance to enhance the effectiveness of the antihistamine. It hasn't really worked yet, but I'm discontinuing early because I think it was disrupting my sleep, and I don't particularly enjoy the acute effects.

I'll talk to my medical provider and try to convince her to give me the higher doses which I originally wanted. Namely, 200-300 mg, with my experience so far suggesting the high end might be appropriate. The highest dose I've found in a study is 400 mg daily; double a normal dose, (1). They found it effective for anxiety, but reported high incidence of sedation as a side effect. In fact, they had a high drop out rate due to "side effects". Sedation appears to be the primary reason larger doses aren't often used for anxiety. Obviously, that is not a side effect in my case. I find it absurd that they don't just try administering the drug at night.

Conclusion: 150 mg of hydroxyzine nightly has improved my subjective sleep quality dramatically. However, beyond a week of administration it failed to enhance sleep schedule or nighttime subjective tiredness. Daytime functioning remains enhanced. I wish to increase my dose to 300-400 mg. My original dose range preference (200-300 mg) was based on anecdotes. This study has me thinking that 300-400 mg may be a better range because some patients only reported mild, as opposed to marked, sedation on 400mg daily.

UPDATE 2: I've been taking the same dose for over a month now. No change from week two. I tried 200 mg for several nights (my prescription is still only 150 mg), and it seemed moderately more effective, but I didn't take that dose long enough to develop peak tolerance.

(1) http://www.sciencedirect.com/science/article/pii/0010440X70900064?via%3Dihub

(2) Tolerance to daytime sedative effects of H1 antihistamines. https://www.ncbi.nlm.nih.gov/pubmed/12352276

20170605

Perhaps blood volume insufficiency is a major cause of migraine.

"The occurrence of migraine in women is influenced by hormonal changes throughout the lifecycle. A beneficial effect of pregnancy on migraine, mainly during the last 2 trimesters, has been observed in 55 to 90% of women who are pregnant", (1). Why do two thirds of pregnant migraineurs see an improvement in symptoms? I believe it may be due to the blood volume expansion. However, I have come across a paper that has me questioning the my previous beliefs on the mechanisms of benefits from blood volume expansion, (2). Nevertheless, benefits still clearly seems autonomic in nature, (3). Given that pregnancy doesn't improve sleep in any obvious fashion, the mechanism for migraine improvement appears independent of sleep.
I have been sick for a few days. Headache has been one of the primary symptoms. I experience headaches regularly regardless. I almost never experience tension headaches (or, rather, what feel like tension headaches). Interestingly, however, during my sick period my headaches were worse during orthostasis (standing). The throb was very dramatic; I could feel each heart beat precisely. My supine (lying down) heart rate was 100 bpm. I didn't measure my orthostatic heart rate. Orthostatic headaches were more persistent than supine ones. In fact, the majority of supine headaches lasted only a dozen or so heartbeats, and only initiated due to plopping down on the bed. Retrospectively, nearly all of my everyday headaches may be orthostatic. I would like to see a study on albumin infusion as an attempt to treat migraines. I would expect both sleep-dependent and sleep-independent improvements. I don't know why people so rarely look for/at upstream disease causes and treatment.
FYI, acetaminophen (tylenol) doesn't appear to impair sleep, while NSAIDs (aspirin, ibuprofen) do.
(2) Drug-induced arterial pressure elevation is associated with arousal from NREM sleep in normal volunteers:
http://jap.physiology.org/content/87/3/897.long
(3) Migraine: A Chronic Sympathetic Nervous System Disorder:
http://www.medscape.com/viewarticle/466937_1