Tuesday, July 23, 2013

Melzack & Katz, Pain. Part 17c: Women, pain, and stress

The paper, Pain.

Part 17: The stress of it all Part 17b: Stress and adrenals


We are still carefully pondering the section Melzack and Katz have included on stress and pain, in their paper, Pain. We have learned that cortisol is a double-edged sword. There was a tantalizing suggestion that the endogenous opioid system might have evolved to ameliorate the effects of cortisol. 

The next paragraph is as follows:
"A major clue to the relationships among injury, stress, and pain is that many autoimmune diseases, such as rheumatoid arthritis and scleroderma, are also pain syndromes. Furthermore, more women than men suffer from autoimmune diseases as well as chronic pain syndromes.72 Among the 5% of adults who have an autoimmune disease, two out of three are women. Of particular importance is the change in sex ratios concurrently with changes in sex hormone output as a function of age. Estrogen increases the release of peripheral cytokines, such as gamma-interferon, which in turn produce increased cortisol. This may explain why more females than males suffer from most kinds of chronic pain as well as painful autoimmune diseases such as multiple sclerosis and lupus.72"

Reference 72 goes to Berkley KJHoldcroft A. Sex and gender differences in pain. In: Wall PDMelzack R, eds. Textbook of Pain. Edinburgh: Churchill Livingstone; 1999951965. 

Aha! I will now go and dig out my copy of that thousand-pound textbook. 


Karen Berkley is at Florida State U, in the Dept. of Psychology, and teaches neuroscience. She researches "neural mechanisms of pelvic visceral pain, neural mechanisms of gynecological pain, sex differences in pain, linkages between basic neuroscience and the clinic."

Her publication list on Pubmed includes 94 papers. It looks as though lately she has been investigating sex differences in knee pain. 


[Oddly, under "book chapters," the contribution to Textbook of Pain Now resting to my left, open at page 951, is not listed, although the chapter she co-authored in Handbook of Pain, is... Oh well, an error of omission. We move on.] 

We begin. In the intro, this quote appears: 
"Sexual difference is probably the issue in our time which could be our 'salvation' if we thought it through." - Louise Irigeray 1982 lecturing in Rotterdam
Six comprehensive reviews on pain and sex differences are listed, all from the 90's (see list* below).
They say, "..a continuing analysis and synthesis of the developing evidence is likely to lead to significant advances in our understanding of pain modulation from fetus to old age" and new therapeutic strategies. Four main lines of research have proven useful: epidemiology (e.g., women are more willing to seek help, and to reap benefit from cognitive approaches), psychophysical studies (women have lower pain thresholds, higher ratings, less tolerance), reproductive research (big gender differences here), genetics. [Yeah... about genetics.. there is a lot of variability in human beings. Not everyone fits neatly into the two main dominant sex categories, for example. But I digress.]

Everyone seems to agree women have more pain and lower thresholds for it. 

An interesting tidbit on page 954, about physiology and body composition; Women, on average, relative to men, have a higher percentage of body fat, smaller muscle mass, lower blood pressure... "pain estimates are inversely proportional to resting blood pressure, a situation that, due to higher blood pressure in males, may be one of the contributors to male hypoalgesia relative to females for pain induced by thermal and ischaemic stimuli" (Fillingim & Maixner 1995).

There seems to be consensus around the pelvis being a main focus for development of chronic pain in women. Douglas and Ginsberg 1996, evaluating chest pain, came up with this little list: 
1. Afferent innervation of internal pelvic organs is extensive and mainly by C fibres.  
2. Dorsal root axons of C fibres diverge as they enter the spinal cord, giving rise to long-ranging axonal branches that synapse with dorsal horn neurons along many remote segments above and below their level of entry, including a large component at upper cervical levels. 
3. C-fibres are activated and sensitized by trauma, injury or disease. This peripheral sensitization can persist long after the organ damage abates, thereby helping to maintain central sensitization of dorsal horn neurons and consequent referred hyperalgesia 
4. A greater proportion of the reproductive tract is internal in females than in males (e.g., vaginal canal and cervix versus penis) 
5. Internal female reproductive organs are more frequently subject to trauma, injury and disease than those in men (e.g., vagina - tampons, intercourse, examination, parturition; uterus - periodic strong contractions, pregnancy, parturition) 
6. Uterine disorders give rise to widespread hyperalgesia much greater in muscles than in skin (Giamberardino et al 1997). 

Hmmnn.. I think we need to remember this list was devised by males... so they could be projecting some unconscious misogyny, pretty much hard-wired into instinctive salience perceptions of "other"-as-threat, I think, then ameliorated or exacerbated by culture, depending which kind we happen to be born into..

However, the list seems logical and the points it makes, accurate; it's endorsed and reproduced in the chapter by these two women whose research lives are completely driven by sex and gender differences in pain; furthermore, evolution is not very bright sometimes.. all it cares about (metaphorically speaking, because it doesn't really "care" about anything) is keeping a species going for as long as thermodynamically possible. If a member of a species lives long enough to reproduce, that's usually good enough from evolution's point of view. It doesn't care about "pain," in fact, pain as a protective emergence is usually beneficial to survival, not a detriment - furthermore, evolution doesn't give a rat's behind for pain perception. It could well be that in lots of ways, for pain in females, evolution has been a great big blind stupid sexist bully. 
[I don't regret never having had children, not for one second. Take that, evolution.] 

Returning to the topic of stress:
The authors discuss progress in psychoneuroimmunology;
1. the hypothalamic-pituitary axis, which while most well known for the integration of sexual and reproductive functions, is differentially affected by stress in males and females (Aloisi et al 1996, Aloisi 1997)
2. Exercise-induced cardiovascular, respiratory and pain responses, studied mainly in the context of angina, that differ in males and females (Forslund et al 1998).
3. Mechanisms of stress-induced analgesia that exhibit sex differences in opiate/non-opiate involvement (Sternberg et al 1995, Sternberg & Liebeskind 1995). 

A fourth is added, stress resulting from major life events accompanied by changes in sex steroid hormones, i.e., puberty, pregnancy, parturition, menopause, andropause (Jones 1997).

A long section on sex steroid hormones is next. They have organizing or activating effects. Organizing effects have to do with embryonic development. Genomic - this is where a sex steroid acts via intracellular messengers to affect gene transcription. Non-genomic - sex steroids work directly on cell membrane receptors. Another aspect has to do with overall sex differences in the "soup" flavour or balance of all the various sex hormones in any given human body. A third aspect has to do with their effects over a lifespan as it rises, then falls - embryo, puberty, fertile adulthood, senescence. Effects are pervasive. Sex hormones modify every organ including the CNS in all sorts of ways that aren't yet clearly understood. The authors list five hormonal influences on pain:

1. metabolism (implications for drug action)
2. immune system (autoimmune diseases are up to nine times more common in women, Fox 1995)  
3. trauma-induced inflammation Ashcroft et al 1997, Roof et al 1997)
4. HPA axis (stress, pain, cardiovascular variables - Fillingim & Maixner 1995))
5. neuroactive agents 

Did you see that?? Nine times. Auto-immune diseases. Women.  

Nobody really knows much (bearing in mind that this chapter was published 14 years ago, and things may have changed by now) about the effects of sex hormones including supplemented ones, on pain experience. Why? "failure until recently of most studies on pain, whether animal or human, experimental or clinical, to take these factors into account."- p. 955 But assay methods are being developed (Stern and McClintock 1996). On the plus side hormone therapy seems to be useful for treating many kinds of painful conditions. 

Sex hormone differences in brains are discussed.. morphological differences, gene expression for central sensitization, sensitivity to morphine, organization of the sympathetic nervous system and 
(facilitative) neuromodulation thereof by agents like nitric oxide and purinergic molecules, motor systems in the brain, effects on neuroplasticity. 

A large chunk of the chapter is about sociocultural influences (i.e., context). Here be all the dragons of sexism, management of "females" and our fertility by societal and cultural structure, institutional mechanisms; add to that, lifestyle. 

Add to that, the physicality of reproduction itself. Clearly, assessment of pain in any female should include parturition history.   

Three broad categories of therapeutic interventions are "drugs, somatic manipulations, and situational adjustments." - p. 960
About drugs, topics addressed include 
  • potential sources of sex differences in drug action
  • adverse drug events
  • implications for drugs currently in use for pain
  • future drug development and clinical trials
About physical and cognitive therapies, "women are generally more willing to use them" - p 961. 
About situational manipulations [which includes pain education] in the case of chronic pain, "there is much evidence that they reduce it by changing expectations, enhancing productive activity and improving quality of life." 
The best solution seems to be a mix of all three. 

Anyway, it's a long chapter, with two full pages of dense, tiny-font reference lists. 
My take-away from it is, if you are going to be born as a human on the planet who doesn't want to end up with chronic pain, be born male if possible - your lifespan may be shorter but on average it is likely to be less chronically painful. Pick your gene pool well so as to eliminate common auto-immune diseases - if you're born female, you are 9 times as likely to have one of these. If you're born female, don't have any children - there are many ways to prevent that (as long as you happen to be a privileged Western European or North American. I.e., don't be born anywhere else on the planet. Don't be born into any culture, or even visit any culture, where rape is automatically, legally, considered to be your own fault.)  

1. Fillingim, R.B. and Maixner, W., Pain Forum, 4(4) (1995) 209-221
2. Psychopharmacology and women: Sex, gender, and hormonesJensvold, Margaret F. (Ed); Halbreich, Uriel (Ed); Hamilton, Jean A. (Ed) Arlington, VA, US: American Psychiatric Association. (1996). xv 599 pp.
3. Unruh, AM; Gender variations in clinical pain experiencePain. 1996 May-Jun;65(2-3):123-67.
4. Berkley KJ;  Sex differences in painBehav Brain Sci. 1997 Sep;20(3):371-80; discussion 435-513.
5. Ciccone GKHoldcroft ADrugs and sex differences: a review of drugs relating to anaesthesiaBr J Anaesth. 1999 Feb;82(2):255-65. (full text)
6. Riley III JL, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a metaanalysis. Pain 1998;74:181–7


Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7bGate control: "The theory was a leap of faith but it was right!"

Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity

Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9cNeuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics

Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10dConclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10eThe neural network that both comprises and moves "Self" is (only)modified by sensory experience

Part 11We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!

Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12gThe Action-Neuromatrix 

Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14cPW Nathan was an interesting pain researcher  Part 14dBrain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input 14i: molecular mediators large and small Part 14j: Neurons, calling glia (over, do you read?) Part 14k: Glia calling glia, over. Do you read? Part 14l: satellite cell and neuron cell body interactions, and we're outta here!

Part 15: Prevention of neurobiological hoarding behaviour by dorsal horn and DRG glia is easier than clutter-busting after the fact

Part 16: Apples are to fruit as cows are to animals as nociceptive input is to pain

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