When a cause cannot be found

Artikkel som nevner mye av problemen rundt behandling av f.eks. ikke-spesifikke ryggplager, IBS eller firbomyalgi. Dette er plager det ikke er noe tydelig årsak-virkning forhold, som ikke kan forklares med et molekyl eller anatomisk utgangspunkt som er felles for alle som har disse plagene, og hvor det ikke er noe klart skille mellom kropp og sinn.

https://raniblogsaboutcausation.wordpress.com/2014/08/14/when-a-cause-cannot-be-found/

This is not a small problem in medicine. By some estimates, such unexplained conditions amount to 30 percent of all symptoms reported to doctors, and they are linked to a 20-50% increase in outpatient costs and a 30% increase in hospitalisation.

This is, basically, what evidence based medicine means: statistical evidence from population studies are applied directly to a patient. This means that each patient is treated as a statistical average, not as a unique individual.

Rather than being dismissed as marginal, therefore, these unexplained conditions should be taken as exemplary for understanding health and disease in general.

Effectiveness of myofascial release: Systematic review of randomized controlled trials

Denne viser til en økende grad av kvalitet på studier på myofascial release, som Strukturell Integrering er. Konklusjonen er at det er god evidens for å bruke dette mot mange muskel- og ledd smertetilstander, og at denne behandlingsformen faktisk kan konkurrere med andre behandlingsformer.

http://www.bodyworkmovementtherapies.com/article/S1360-8592(14)00086-2/fulltext

Seventeen studies were with higher methodological quality and the remaining 2 were of moderate quality, which is appreciable for a relatively new approach with considerable amount of practice variations.

The results of the studies were encouraging, particularly with the recently published studies. In many RCT’s the MFR was adjunctive to other treatments and the potential-specific MFR effect cannot be judged.

Nine studies concluded that MFR may be better than no treatment or sham treatment for various musculoskeletal and painful conditions. Seven studies demonstrated that MFR with a conventional therapy is more effective than a control group receiving no treatment (3 studies), sham treatment (1 study) or with a conventional therapy.

There is evidence that MFR alone or added to other conventional therapies, relieves pain and improves function not lesser than conventional therapies studied. According to these results, MFR may be useful as either a unique therapy or as an adjunct therapy to other established therapies for a variety of conditions like sub acute low back pain, fibromyalgia, lateral epicondylitis, plantar fasciitis, headache, fatigue in breast cancer, pelvic rotation, hamstring tightness etc.

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Denne beskriver endocannabinoider(eCB) og hvordan man kan øke produksjonen av dem og reseptorene for dem. eCB er et kroppens viktigste naturlige smertstillende stoffer som kan produseres og påvirker alle nerver i kroppen. Spesielt viktig i hjernen, men også i det perifere nervesystem.

Massasje, kiropraktikk og hard trening (f.eks. runners high) utløser eCB i kroppen. Det gjør også omegabalanse (mer n-3), probiotica, NSAIDs, m.m. Også yoga, meditasjon, pust og andre stressreduserende påvirker eCB. Og trening, men kun om man gjør det jevnlig over tid.

Den nevner at langvarig stress reduserer eCB i kroppen siden det er koblet til kortisol. Men den nevner også at noen tilstander kan ha forhøyet eCB i kroppen, f.eks. overvekt.

Med høyt nivå av n-6 relativt til n-3 blir det en overvekt av AA (arakidonsyre) som produserer en overvekt av eCB, som dermed fører til en reduksjon av eCB reseptorer. Dette gjør at smertestillende medikamenter fungerer dårligere, og at det blir lettere kronisk smerte. Tilskudd av n-3 gjør at eCB reseptorene øker. Studiene er gjort på mus og innebærer 17 g/kg.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089566

The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. Metaphorically the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine. Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with particularly dense expression in (rank order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala [1]. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous [2][3].

The eCB system’s salient homeostatic roles have been summarized as, “relax, eat, sleep, forget, and protect” [5]. It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism. Obese individuals seem to display an increased eCB tone, driving CB1activation in a chronic, feed-forward dysfunction (reviewed by [6]).

Other diseases are associated with suboptimal functioning of the eCB system. Russo [8]proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride [9] speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka [10] hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia [11], migraine [12], multiple sclerosis [13], Huntington’s [14],[15], uncompensated Parkinson’s [16], irritable bowel syndrome [17], uncompensated anorexia[18], and chronic motion sickness [19].

NSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine [27]. SeeFigure 2. A binding site for some NSAIDs on FAAH has also been identified [28]. NSAID inhibition of COX2 blocks the metabolism of AEA and 2-AG into prostaglandin ethanolamides (PG-EAs) and prostaglandin glycerol esters (PG-GEs), respectively [29].

Combining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects. A sub-effective dose of WIN55,212-2 became fully antinociceptive following administration of indomethacin in rats [36].

In summary, preclinical studies indicate that some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Combinational effects may be particularly relevant at peripheral sites, such as the peripheral terminals of nociceptors.

The distribution of glucocorticoid receptors (GRs) and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoid-mediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects.

The acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain.

Chronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus [59] and mouse hippocampus and amygdala [61]. Chronic corticosterone administration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [62].

Polyunsaturated fatty acids (PUFAs) play fundamental roles in many cellular and multicellular processes, including inflammation, immunity, and neurotransmission. They must be obtained through diet, and a proper balance between omega-6 (ω-6) PUFAs and ω-3 PUFAs is essential. The typical Western diet contains a surfeit of ω-6s and a deficiency of ω-3s [130].

The inflammatory metabolites of AA are countered by dietary ω-3s. The two best-known ω-3s are eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 22:6ω-3).

eCBs are derived from AA (see Figure 2). Several preclinical studies showed that dietary supplementation with AA increased serum levels of AEA and 2-AG, summarized in Table 1. Although we clearly need AA to biosynthesize eCBs, excessive levels of AA, administered chronically, may lead to excessive levels of eCBs. This in turn may lead to desensitized and downregulated CB1 and CB2 receptors.

Dietary supplementation with ω-3s predictably increased the concentration of EPA and/or DHA in tissues, cells, and plasma, and decreased the relative concentration of AA in tissues, cells, and plasma [132][133]. ω-3 supplementation also decreased AEA and 2-AG in tissues, cells, and plasma (Table 1).

Adequate levels of dietary ω-3s are required for proper eCB signaling. Mice supplemented with ω-3s, compared to mice on a control diet, expressed greater levels of CB1 and CB2 mRNA.

n summary, dietary ω-3s seem to act as homeostatic regulators of the eCB system. In obese rodents fed a high-AA diet, ω-3s significantly decrease eCBs, especially 2-AG, particularly in tissues that become dysregulated, such as adipose and liver tissues. Plasma eCB levels are reduced by krill oil also in obese humans. Little change in eCB levels are seen in normo-weight individuals not fed a high ω-6 diet, and dietary ω-3s are required for proper eCB signaling.

Human intestinal epithelial cells incubated with L. acidophilus produced more CB2 mRNA [145]. Feeding L. acidophilus to mice and rats increased the expression of CB2 mRNA in colonic epithelial cells. Lastly, mice fed L. acidophilus showed less pain behavior following colonic distension with butyrate than control mice, an effect reversed by the CB2 antagonist AM630[145].

Chronic or repeated stress results in a chronic elevation of endogenous corticosterone via the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic stress (repeated restraint) reduced AEA levels throughout the corticolimbic stress circuit in rodents [99][196][197].

In summary, chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG. Changes in CB1 expression are more labile. Stress management may reverse the effects of chronic stress on eCB signaling, although few studies exploring this possibility have been performed to date. Clinical anecdotes suggests that stress-reduction techniques, such as meditation, yoga, and deep breathing exercises impart mild cannabimimetic effects [218].

Massage and osteopathic manipulation of asymptomatic participants increased serum AEA 168% over pretreatment levels; mean OEA levels decreased 27%, and no changes occurred in 2-AG. Participants receiving sham manipulation showed no changes [218].

Upregulation of the eCB system in obese humans seems to be driven by excessive production of eCBs in several peripheral tissues such as visceral adipose tissue, liver, pancreas, and skeletal muscle.

In summary, increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.

Although both types of exercise regimens increased eCB ligand concentrations, only long-term-forced exercise led to sustained elevations of eCBs, and predictable CB1 downregulation.

In whole animals, however, caffeine’s effects are biphasic and vary by dosage and acute versus chronic administration. In humans, the acute administration of caffeine decreases headache pain, but exposure to chronic high doses, ≥300 mg/day, may exacerbate chronic pain [275].

The Mechanisms of Manual Therapy in the Treatment of Musculoskeletal Pain: A Comprehensive Model

Nevner det meste rundt behandling av muskel og skjelett problemer, både usikkerheter, manglende diagnostisk spesifisitet, dårlig forhold mellom forklaringsmodelle og realitet, og foreslår nevrosentriske forklaringsmodeller. Viser til at spesifikk behandling ikke har bedre effekt enn uspesifikk behandling. Og til at den mekaniske teknikken setter igang en kaskade av nevrologiske effekter som resulterer i en behandlingeffekt.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775050/

Abstract

Prior studies suggest manual therapy (MT) as effective in the treatment of musculoskeletal pain; however, the mechanisms through which MT exerts its effects are not established. In this paper we present a comprehensive model to direct future studies in MT. This model provides visualization of potential individual mechanisms of MT that the current literature suggests as pertinent and provides a framework for the consideration of the potential interaction between these individual mechanisms. Specifically, this model suggests that a mechanical force from MT initiates a cascade of neurophysiological responses from the peripheral and central nervous system which are then responsible for the clinical outcomes. This model provides clear direction so that future studies may provide appropriate methodology to account for multiple potential pertinent mechanisms.

Mechanical Stimulus 

First, only transient biomechanical effects are supported by studies which quantify motion (Colloca et al., 2006;Gal et al., 1997;Coppieters & Butler, 2007;Coppieters & Alshami, 2007) but not a lasting positional change (Tullberg et al., 1998;Hsieh et al., 2002). Second, biomechanical assessment is not reliable. Palpation for position and movement faults has demonstrated poor reliability (Seffinger et al., 2004;Troyanovich et al., 1998) suggesting an inability to accurately determine a specific area requiring MT.  Third, MT techniques lack precision as nerve biased techniques are not specific to a single nerve (Kleinrensink et al., 2000) and joint biased technique forces are dissipated over a large area (Herzog et al., 2001;Ross et al., 2004).

Finally, studies have reported improvements in signs and symptoms away from the site of application such as treating cervical pain with MT directed to the thoracic spine (Cleland et al., 2005;Cleland et al., 2007) and lateral epicondylitis with MT directed to the cervical spine (Vicenzino et al., 1996).

Subsequently, we suggest, that as illustrated by the model, a mechanical force is necessary to initiate a chain of neurophysiological responses which produce the outcomes associated with MT. 

Neurophysiological Mechanism 

Studies have measured associated responses of hypoalgesia and sympathetic activity following MT to suggest a mechanism of action mediated by the periaquaductal gray (Wright, 1995) and lessening of temporal summation following MT to suggest a mechanism mediated by the dorsal horn of the spinal cord (George et al., 2006) The model makes use of directly measurable associated responses to imply specific neurophysiological mechanisms when direct observations are not possible. The model categorizes neurophysiological mechanisms as those likely originating from a peripheral mechanism, spinal cord mechanisms, and/or supraspinal mechanisms.

Peripheral mechanism 

Musculoskeletal injuries induce an inflammatory response in the periphery which initiates the healing process and influences pain processing. Inflammatory mediators and peripheral nociceptors interact in response to injury and MT may directly affect this process. For example, (Teodorczyk-Injeyan et al., 2006) observed a significant reduction of blood and serum level cytokines in individuals receiving joint biased MT which was not observed in those receiving sham MT or in a control group. Additionally, changes of blood levels of β-endorphin, anandamide, N-palmitoylethanolamide, serotonin, (Degenhardt et al., 2007) and endogenous cannabinoids (McPartland et al., 2005) have been observed following MT. Finally, soft tissue biased MT has been shown to alter acute inflammation in response to exercise (Smith et al., 1994) and substance P levels in individuals with fibromyalgia (Field et al., 2002). Collectively, these studies suggest a potential mechanism of action of MT on musculoskeletal pain mediated by the peripheral nervous system for which mechanistic studies may wish to account. 

Spinal mechanisms 

MT may exert an effect on the spinal cord. For example, MT has been suggested to act as a counter irritant to modulate pain (Boal & Gillette, 2004) and joint biased MT is speculated to “bombard the central nervous system with sensory input from the muscle proprioceptors (Pickar & Wheeler, 2001).”Subsequently, a spinal cord mediated mechanism of MT must be considered and is accounted for in the model. Direct evidence for such an effect comes from a study (Malisza et al., 2003b) in which joint biased MT was applied to the lower extremity of rats following capsaicin injection. A spinal cord response was quantified by functional MRI during light touch to the hind paw. A trend was noted towards decreased activation of the dorsal horn of the spinal cord following the MT. The model uses associated neuromuscular responses following MT to provide indirect evidence for a spinal cord mediated mechanism. For example, MT is associated with hypoalgesia (George et al., 2006;Mohammadian et al., 2004;Vicenzino et al., 2001), afferent discharge (Colloca et al., 2000;Colloca et al., 2003), motoneuron pool activity (Bulbulian et al., 2002;Dishman & Burke, 2003), and changes in muscle activity (Herzog et al., 1999;Symons et al., 2000) all of which may indirectly implicate a spinal cord mediated effect.

Supraspinal mechanisms 

Finally, the pain literature suggests the influence of specific supraspinal structures in response to pain. Structures such as the anterior cingular cortex (ACC), amygdala, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) are considered instrumental in the pain experience.(Peyron et al., 2000;Vogt et al., 1996;Derbyshire et al., 1997;Iadarola et al., 1998;Hsieh et al., 1995;Oshiro et al., 2007;Moulton et al., 2005;Staud et al., 2007;Bee & Dickenson, 2007;Guo et al., 2006). Subsequently, the model considers potential supraspinal mechanisms of MT. Direct support for a supraspinal mechanism of action of MT comes from (Malisza et al., 2003a) who applied joint biased MT to the lower extremity of rats following capsaicin injection. Functional MRI of the supraspinal region quantified the response of the hind paw to light touch following the injection. A trend was noted towards decreased activation of the supraspinal regions responsible for central pain processing. The model accounts for direct measures of supraspinal activity along with associated responses such as autonomic responses (Moulson & Watson, 2006;Sterling et al., 2001;Vicenzino et al., 1998) (Delaney et al., 2002;Zhang et al., 2006), and opiod responses (Vernon et al., 1986) (Kaada & Torsteinbo, 1989) to indirectly imply a supraspinal mechanism. Additionally, variables such as placebo, expectation, and psychosocial factors may be pertinent in the mechanisms of MT (Ernst, 2000;Kaptchuk, 2002). For example expectation for the effectiveness of MT is associated with functional outcomes (Kalauokalani et al., 2001) and a recent systematic review of the literature has noted that joint biased MT is associated with improved psychological outcomes (Williams et al., 2007). For this paper we categorize such factors as neurophysiological effects related to supraspinal descending inhibition due to associated changes in the opioid system (Sauro & Greenberg, 2005), dopamine production (Fuente-Fernandez et al., 2006), and central nervous system (Petrovic et al., 2002;Wager et al., 2004;Matre et al., 2006) which have been observed in studies unrelated to MT.

Figure 3 Pathway considering both a spinal cord and supraspinal mediated effect from Bialosky et al (2008)

to studier på hvordan huden reagerer på trykkømhet

To studier på hvordan huden påvirker trykksensitivitet.

Ene nevner at trykkømhet i fibromyalgi er værst over der en nerve er, ikke så mye over knokler eller muskler.  Nevner at en bedøvende krem på huden ikke endrer trykkømhet.

Andre nevner at trykkømhet normalt faktisk blir mindre av en bedøvende krem, og bekrefter at ømheten er større over en nervebane enn over knokkel eller muskel.

Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue

http://www.sciencedirect.com/science/article/pii/0304395996000127

The site with underlying nerve had a lower PPT than the bony site (P > 0.001) and the ‘pure’ muscle site (P > 0.001), respectively. These relations remained unaltered by skin hypoesthesia.

Application of EMLA, compared to control cream, did not change PPTs over any area examined. The results demonstrated that pressure-induced pain sensibility in FM patients is not most pronounced in muscle tissue and does not depend on increased skin sensibility.

Pressure pain thresholds in different tissues in one body region. The influence of skin sensitivity in pressure algometry.

http://www.ncbi.nlm.nih.gov/m/pubmed/10380724

The PPT was significantly (p < 0.001) lower at the «muscle/nerve» site than at the bony and «pure» muscle sites.

However, PPTs after control cream were lower (p < 0.001) over all examined areas than those obtained prior to cream application. Thus, EMLA cream increased PPTs compared to control sites in all examined areas (p < 0.001). Under the given circumstances, skin pressure pain sensitivity was demonstrated to influence the PPT.

A new view on hypocortisolism

Om lavt kortisol-nivå og at det har en beskyttende effekt på kroppen etter langvarig høyt kortisol-nivå. En ny måte å se det på. Det er faktisk en overlevelsesmekanisme. Hvis vi ikke greier å skru av stresset eller fjerne oss fra den stressende livssituasjonen, vil kroppen etter hvert skru av stressresponsen og vi blir oversensitive for enhver utfordring. Utmattelse, muskelsmerter og fibromyalgi blir resultatet. Men likevel er det bedre for organismen enn videre stressresons. Studien forteller hvordan kortisol påvirker sentralnervesystemet, immunsystemet, oppvåkningsresponsen om morgenen, sickness responce, allostatic load, m.m.

http://cfids-cab.org/cfs-inform/Hypotheses/fries.etal05.pdf

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post- traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue.

We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic–pituitary– adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Since the work of Selye (1936), stress has been associated with an activation of the hypothalamic– pituitary–adrenal (HPA) axis resulting in an increased release of cortisol from the adrenal glands. In recent years, a phenomenon has been described that is characterized by a hyporespon- siveness on different levels of the HPA axis in a number of stress-related states. This phenomenon, termed ‘hypocortisolism’, has been reported in about 20–25% of patients with stress-related dis- orders such as chronic fatigue syndrome (CFS), chronic pelvic pain (CPP), fibromyalgia (FMS), post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), low back pain (LBP), burn- out, and atypical depression (Griep et al., 1998; Heim et al., 1998, 2000; Pruessner et al., 1999; Gold and Chrousos, 2002; Gur et al., 2004; Roberts et al., 2004; Rohleder et al., 2004). When hypo- cortisolemic, all these disorders may share affiliated syndromes characterized by a triad of enhanced stress sensitivity, pain, and fatigue.

However, despite different definitions we know today that there is a considerable overlap between the disorders.

In the early 1990s, Hudson and colleagues were amongst the first addressing this issue. They published a study on the comorbidity of FMS with medical and psychiatric disorders in which they reported a higher prevalence of migraine, IBS, and CFS, as well as higher lifetime rates of depression and panic disorder in patients with FMS (Hudson et al., 1992).

Thus, numerous studies on male war veterans have reported an association between PTSD and symp- toms such as fatigue, joint pain, and muscle pain (Engel et al., 2000; Ford et al., 2001).

These alterations of HPA axis are determined by (1) a reduced biosynthesis or release of the respective releasing factor/hormone on different levels of the HPA axis (CRF/AVP from the hypothalamus, ACTH from the pituitary, or cortisol from the adrenal glands) accompanied by a subsequent decreased stimulation of the respective target receptors, (2) a hypersecretion of one secretagogue with a subsequent down-regulation of the respective target receptors, (3) an enhanced sensitivity to the negative feedback of glucocorti- coids, (4) a decreased availability of free cortisol, and/ or (5) reduced effects of cortisol on the target tissue, describing a relative cortisol resistance (Heim et al., 2000; Raison and Miller, 2003).

Several years ago we postulated that hypocortiso- lism/a hyporeactive HPA axis might develop after prolonged periods of stress together with a hyper- activity of the HPA axis and excessive glucocorti- coid release (Hellhammer and Wade, 1993). This proposed time course with changes in HPA axis activity from hyper- to hypocortisolism resembles the history of patients with stress-related disorders who frequently report about the onset of ‘hypo- cortisolemic symptoms’ (fatigue, pain, stress sen- sitivity) after prolonged periods of stress, e.g. work stress, infection, or social stress (Buskila et al., 1998; Van Houdenhove and Egle, 2004)

Thinking about the potential cause/reason for changes in HPA axis activity from hyper- to hypocortisolism one might consider the body’s self-adjusting abilities as an important factor. Self-adjusting abilities play a significant role in survival of the organism by counteracting the enduring increased levels of glucocorticoids, and protecting the organism against the possible dele- terious effects thereof.

Poten- tial mechanisms of the ‘HPA axis adjustment’ are (1) the down-regulation of specific receptors on different levels of the axis (hypothalamus, pitu- itary, adrenals, target cells), (2) reduced biosyn- thesis or depletion at several levels of the HPA axis (CRF, ACTH, cortisol) and/or (3) increased negative feedback sensitivity to glucocorticoids (Hellhammer and Wade, 1993; Heim et al., 2000).

The suppressed stress response after administration of dexamethasone demonstrates an increased sensi- tivity to glucocorticoid negative feedback on the level of the pituitary.

The duration, intensity, number and chronicity of stressors may further pronounce these effects. The low-dose dexamethasone test may be the most sensitive measure of this condition.

The HPA axis plays an important role in the regulation of the SNS. CRF seems to increase the spontaneous discharge rate of locus coeruleus (LC) neurons and enhances norepinephrine (NE) release in the prefrontal cortex (Valentino, 1988; Valentino et al., 1993; Smagin et al., 1995), whereas glucocorticoids seem to exert more inhibitory effects on NE release.

Glucocorticoids are the most potent anti-inflam- matory hormones in the body. They act on the immune system by both suppressing and stimulating pro- and anti-inflammatory mediators. While they promote Th2 development, for example by enhan- cing interleukin (IL)-4 and (IL)-10 secretion by macrophages and Th2 cells (Ramierz et al., 1996), they inhibit inflammatory responses and suppress the production and release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF- alpha), IL-1 and IL-6 (see Franchimont et al., 2003).

An important role of glucocorticoids during stress is to suppress the production and activity of pro- inflammatory cytokines, thus restraining the inflammatory reaction and preventing tissue destruction (see McEwen et al., 1997; Ruzek et al., 1999; Franchimont et al., 2003).

Therefore, a hypocortisolemic stress response, as observed in patients with stress-related disorders, may result in an overactivity of the immune system in terms of increased inflammatory responses due to impaired suppressive effects of low cortisol levels (see Heim et al., 2000; Rohleder et al., 2004). This assumption is supported by studies reporting elevated levels of pro-inflammatory cytokines in patients with stress-related disorders such as PTSD, CFS, and FMS (Maes et al., 1999; Patarca-Montero et al., 2001; Thompson and Barkhuizen, 2003; Rohleder et al., 2004).

Assessing the cortisol awakening response in pregnant women, preliminary results from our laboratory suggest that women with higher daily stress load showed lower cortisol levels in the morning compared to women with normal to low daily stress load. This result suggests a possible prevention of harmful stimulatory effects of maternal cortisol on placental CRF, which plays a major role in the initiation of delivery (Rieger, 2005).

The term ‘sickness response’ refers to non-specific symptoms such as fatigue, increased pain sensi- tivity, depressed activity, concentration difficul- ties, and anorexia that accompany the response to infection (Hart, 1988; Maier and Watkins, 1998). Sickness behavior at the behavioral level appears to be the expression of a central motivational state that reorganizes the organism’s priority to cope with infectious pathogens (Hart, 1988).

Further evidence for the protective effects of the development of a hypocortisolism refers to the allostatic load index. The term ‘allostatic load’ was irstly introduced by McEwen and Stellar (1993) describing the wear and tear of the body and brain resulting from chronic overactivity or inactivity of physiological systems that are normally involved in adaptation to environmental challenge. Allostatic load results when the allostatic systems (e.g. the HPA axis) are either overworked or fail to shut off after the stressful event is over or when these systems fail to respond adequately to the initial challenge, leading other systems to overreact (McEwen, 1998). In this context, results of Hell- hammer et al. (2004) demonstrate a significantly higher allostatic load index in older compared to younger subjects with the exception of hypocorti- solemic elderly who had a comparable allostatic load to young people even though they scored far higher on perceived stress scales. Considering the fact that allostatic load has been associated with a higher risk for mortality, these data suggest that a hypocortisolemic response to stress may rather be protective than damaging.

Low cortisol levels in the case of pregnant women may protect the mother and the child against the risk of pre-term birth, which could be harmful for both of them. Similarly, low cortisol levels in those individuals who are repeatedly or continuously exposed to intense immune stimuli may be beneficial for health and survival.

Similarly, low cortisol levels in those individuals who are repeatedly or continuously exposed to intense immune stimuli may be beneficial for health and survival. Most strikingly, the demonstration of a low allostatic load index in hypocortisolemic subjects suggests that a down-regulation of the HPA axis in chroni- cally stressed subjects protects those subjects against the harmful effects of a high allostatic load index.

Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

Om fibromyalgi og at 41% av pasientene har tynnfibernevropati. 3% av kontrollgruppen har det. Tynnfibernevropati-type smerter er en del av mange sykdommer og flere studier viser at det er underdiagnostisert.

http://www.painjournalonline.com/article/S0304-3959(13)00294-7/abstract

No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes.

We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P0.001).

Abnormal AFTs (autonomic function test) were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic.

These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively.