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Immediate effects of region-specific and non-region-specific spinal manipulative therapy in patients with chronic low back pain: a randomized controlled trial.

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Om hvordan en detaljert klinisk undersøkelse egentlig er unødvendig…

http://www.ncbi.nlm.nih.gov/m/pubmed/23431209

BACKGROUND: Manual therapists typically advocate the need for a detailed clinical examination to decide which vertebral level should be manipulated in patients with low back pain. However, it is unclear whether spinal manipulation needs to be specific to a vertebral level.

Both groups improved in terms of immediate decrease of pain intensity; however, no between-group differences were observed.

CONCLUSION: The immediate changes in pain intensity and pressure pain threshold after a single high-velocity manipulation do not differ by region-specific versus non-region-specific manipulation techniques in patients with chronic low back pain.

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Spinal manipulative therapy for low back pain.

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Om hvordan forskjellige behandlingsformer egentlig ikke har så mye forskjellige resultater på smerter…

http://www.ncbi.nlm.nih.gov/m/pubmed/14973958/

Spinal manipulative therapy had no statistically or clinically significant advantage over general practitioner care, analgesics, physical therapy, exercises, or back school. Results for patients with chronic low-back pain were similar.

Radiation of pain, study quality, profession of manipulator, and use of manipulation alone or in combination with other therapies did not affect these results.

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Nociceptors: the sensors of the pain pathway

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Alt om nociceptorer og smerte. Nevner at nedstigende signaler i ryggmargen sender signaler ut i perferien hvor nervetråden utløser betennelser og dermed gir smerte i huden.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964977/

Since enhanced excitability of primary sensory neurons in inflammatory and pathologic pain states is a major contributor to the perception of pain, specific pharmacological agents that specifically dampen aberrant activity are desirable in the design of pain therapeutics.

Anatomy of nociceptors.

(A) Somatosensory neurons are located in peripheral ganglia (trigeminal and dorsal root ganglia) located alongside the spinal column and medulla. Afferent neurons project centrally to the brainstem (Vc) and dorsal horn of the spinal cord and peripherally to the skin and other organs. Vc, trigeminal brainstem sensory subnucleus caudalis. (B) Most nociceptors are unmyelinated with small diameter axons (C-fibers, red). Their peripheral afferent innervates the skin (dermis and/or epidermis) and central process projects to superficial laminae I and II of the dorsal horn. (C) A-fiber nociceptors are myelinated and usually have conduction velocities in the Aδ range (red). A-fiber nociceptors project to superficial laminae I and V.

Pain, as a submodality of somatic sensation, has been defined as a “complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and manifested by certain autonomic, psychological, and behavioral reactions” (1).

Normally, nociception (see Glossary, Sidebar 1) and the perception of pain are evoked only at pressures and temperatures extreme enough to potentially injure tissues and by toxic molecules and inflammatory mediators.

Pain is described as having different qualities and temporal features depending on the modality and locality of the stimulus, respectively: first pain is described as lancinating, stabbing, or pricking; second pain is more pervasive and includes burning, throbbing, cramping, and aching and recruits sustained affective components with descriptors such as “sickening” (3).

As opposed to the relatively more objective nature of other senses, pain is highly individual and subjective (4, 5) and the translation of nociception into pain perception can be curtailed by stress or exacerbated by anticipation (6).

Adequate stimuli include temperature extremes (> ~40°C–45°C or < ~15°C), intense pressure, and chemicals signaling potential or actual tissue damage. Nociceptors are generally electrically silent (12) and transmit all-or-none action potentials only when stimulated.

However, nociceptor activity does not per se lead to the perception of pain. The latter requires peripheral information to reach higher centers and normally depends on the frequency of action potentials in primary afferents, temporal summation of pre- and postsynaptic signals, and central influences (7).

Most nociceptors have small diameter unmyelinated axons (C-fibers) (12) bundled in fascicles surrounded by Schwann cells and support conduction velocities of 0.4–1.4 m/s (22) (Figure ​(Figure1).1). Initial fast-onset pain is mediated by A-fiber nociceptors whose axons are myelinated and support conduction velocities of approximately 5–30 m/s (most in the slower Aδ range) (22).

Noxious stimuli are transduced into electrical signals in free “unencapsulated” nerve endings that have branched from the main axon and terminate in the wall of arterioles and surrounding connective tissue, and may innervate distinct regions in the dermis and epidermis (17, 30). The endings are ensheathed by Schwann cells except at the end bulb and at mitochondria- and vesicle-rich varicosities (17). A–fibers lose their myelin sheath and the unmyelinated A-fiber branches cluster in separated small spots within a small area, the anatomical substrate for their receptive field (17). C-fiber branches are generally more broadly distributed, precluding precise localization of the stimulus (17).

In contrast, specialized nonneuronal structures conferring high sensitivity to light touch, stretch, vibration, and hair movement are innervated by low threshold A-fibers (11).

They terminate predominantly in laminae I, II, and V of the dorsal horn on relay neurons and local interneurons important for signal modification (13, 37, 38) (Figure ​(Figure1,1, B and C). The relay neurons project to the medulla, mesencephalon, and thalamus, which in turn project to somatosensory and anterior cingulate cortices to drive sensory-discriminative and affective-cognitive aspects of pain, respectively (38). Local inhibitory and excitatory interneurons in the dorsal horn as well as descending inhibitory and facilitatory pathways originating in the brain modulate the transmission of nociceptive signals, thus contributing to the prioritization of pain perception relative to other competing behavioral needs and homeostatic demands (39).

Whereas heat- and chemical-induced nociceptor responses correlate with pain perception in humans (9,24), mechanical stimulation of C-MH (24) and rapidly adapting A-HTM (18) fibers may not (24) (Tables​(Tables11 and ​and2).2).

To this end, an understanding of species-specific differences is critical, as exemplified by the dramatically different phenotypes in mice and humans lacking Nav1.7: although mice lacking Nav1.7 show a mechanosensory (pinch) and formalin-induced (5%) pain phenotype (103), humans lacking Nav1.7 are insensitive to pain altogether (104).

Anterograde transmission of action potentials from the spinal cord to the periphery results in release of peptides and other inflammatory mediators in the skin and exacerbates nociceptor excitability and pain (see below). It is at the spinal level that nonnociceptive neurons are recruited by strong nociceptor activation through functional modulation of local circuits (105).

Injury to the skin induces protective physiological responses aimed at decreasing the likelihood of exacerbating the injury. After an injury induced by pungent chemicals (e.g., capsaicin, mustard oil) and burn, stimulation of the injured area produces enhanced pain to noxious stimuli (primary mechanical and thermal hyperalgesia) dependent on C-fiber activity that manifests as a decrease in threshold to activate C-MH fibers and to perceive pain (9, 19, 106). Immediately surrounding the injured area, a zone of flare (reddening) develops and stimulation of even a larger secondary zone produces pain in response to normally innocuous stimuli (e.g., brush stroke) (secondary mechanical allodynia) as well as enhanced responsiveness to noxious mechanical (secondary mechanical hyperalgesia) and thermal (heat) hyperalgesia if spatial summation is invoked (secondary thermal hyperalgesia) (21, 105, 107). Here, noxious punctate stimulation of C-nociceptors induces secondary mechanical hyperalgesia mediated by A-nociceptors (7) and innocuous dynamic mechanical stimuli (gentle stroking) provokes nonnociceptor A-fiber–mediated pain (108). Cellular mechanisms underlying this complicated response involve both peripheral and central processes (14, 38, 105, 107) and require nociceptor input, particularly A-MH and C-MH fibers (19, 91, 105). After a burn, A-MH fibers (most likely type I) mediate primary heat hyperalgesia in glabrous skin (9).

Centrally propagating impulses can antidromically invade peripheral arborizations innervating other areas in the afferent’s receptive field (axon reflex), causing the release of peptides (e.g., substance P, CGRP, somatostatin) and/or other bioactive substances from the terminal (e.g., cytokines) into the interstitial tissue (17). The released substances produce a myriad of autocrine or paracrine effects on endothelial, epithelial, and resident immune cells (Langerhans), which lead to arteriolar vasodilatation (“flare,” via CGRP) and/or increased vascular permeability and plasma extravasation from venules (edema, via substance P). Liberated enzymes (e.g., kallikreins) and blood cells (e.g., platelets, mast cells) further contribute to the accumulation of inflammatory mediators and neurogenic inflammation (110, 111).

A recently described phenomenon (“hyperalgesic priming”) evoked by cytokine- and neurotrophin-induced recruitment of Gi/o-PKCε signaling in nociceptors can produce prolonged sensitization and mechanical hyperalgesia and may contribute to chronic pain (114).

Significant crosstalk between these pathways exists at multiple levels including stimulus transduction (118), peripheral terminals during neurogenic inflammation, and central connections during central sensitization and may underlie paradoxical temperature sensation.

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Can pain change our brain maps?

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Om at området med smerte får en mindre størrelse i Primary Sensory Cortex (S1) i hjernen.

http://www.bodyinmind.org/crpscan-pain-change-our-brain-maps/

That S1 reorganises with pain, and the S1 representation of the CRPS-affected hand is smaller, is widely assumed and accepted.

We found consistent evidence that the representation of the CRPS-affected hand in S1 is smaller than that of the unaffected hand, and that of healthy pain-free controls.

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Allodynia mediated by C-tactile afferents in human hairy skin

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Viktig studie med alt om hudens c-fibre og deres relasjon til smerte (allodynia). Nevner at det er en samling av flere mekanoreseptorer i både muskel og hud som gir opphav smerte, ikke enkeltvis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180003/ 

We show that gentle tactile stimulation (vibration and brushing) of the hairy skin can exacerbate the underlying muscle pain (allodynia) evoked by infusion of hypertonic saline into the tibialis anterior muscle. This effect is dependent upon a low-threshold, mechanosensitive class of nerve fibres in the hairy skin known as C-tactile (CT) fibres. Knowledge of the role of CT fibres in allodynia increases our understanding of the mechanisms that underlie sensory-perceptual abnormalities – a common manifestation of clinical-pain states and neurological disorders.

We recently showed a contribution of low-threshold cutaneous mechanoreceptors to vibration-evoked changes in the perception of muscle pain. Neutral-touch stimulation (vibration) of the hairy skin during underlying muscle pain evoked an overall increase in pain intensity, i.e. allodynia. This effect appeared to be dependent upon cutaneous afferents, as allodynia was abolished by intradermal anaesthesia.
 Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into tibialis anterior muscle (TA). Sinusoidal vibration (200 Hz–200 μm) was applied to the hairy skin overlying TA. Pain ratings were recorded using a visual analogue scale (VAS).
During tonic muscle pain (VAS 4–6), vibration evoked a significant and reproducible increase in muscle pain (allodynia) that persisted following compression of myelinated afferents. During compression block, the sense of vibration was abolished, but the vibration-evoked allodynia persisted.  In contrast, selective anaesthesia of unmyelinated cutaneous afferents abolished the allodynia, whereas the percept of vibration remained unaffected.
It is widely accepted that discriminative touch is mediated exclusively by large-diameter sensory fibres, whereas painful sensations are mediated by small-diameter fibres. Consistent with this view, selective microstimulation of a single large-diameter myelinated afferent in awake human subjects evokes a fundamental, innocuous (non-painful) sensation that has the quality of pressure, flutter or vibration according to the type of primary afferent excited (Ochoa & Torebjork, 1983; Vallbo et al. 1984; Macefield et al. 1990).
In addition to cutaneous nociceptors, which have high mechanical thresholds, there is another class of unmyelinated (C) fibre that has low mechanical thresholds. The existence of low-threshold unmyelinated afferents, termed C-mechanoreceptors, which respond to light touch of the skin, was documented long ago in the hairy skin of the cat and monkey (Zotterman, 1939; Maruhashi et al. 1952; Douglas & Ritchie, 1957; Bessou et al. 1971). Although some investigators had suggested that C low-threshold mechanoreceptors (CLTMs) are vestigial (Kumazawa & Perl, 1977), recent studies have reported a class of unmyelinated fibres in the human hairy skin, known as C-tactile (CT) fibres, that responds to innocuous mechanical stimulation (Johansson et al. 1988; Nordin, 1990; Vallbo et al.1993).
The response properties of CT fibres have been described using a limited range of stimuli – most notably slowly moving, low-force, mechanical stimuli such as finger stroking and soft brushing (Nordin, 1990; Vallbo et al. 1993, 1999; Lokenet al. 2009).
 It is this latter observation, together with the results of neuroimaging studies that have demonstrated that CT-mediated inputs project onto the insular cortex, which has underpinned the proposition of a CT-mediated emotional touch system (Olausson et al. 2002; Cole et al. 2006;McGlone et al. 2007; Olausson et al. 2008).  Intriguingly, in healthy subjects gentle brushing – known to elicit CT fibre responses – can evoke a neutral or even unpleasant sensation at the lowest brushing velocities (Loken et al. 2009), suggesting that gentle tactile stimulation can elicit opposing aspects of touch, i.e. predilection and aversion. A contribution of CT fibres to unpleasant touch has been suggested by recent work showing the activation of superficial dorsal horn neurons by gentle brushing of skin (Andrew, 2010; Craig, 2010). Similarly, these fibres have been implicated in touch hypersensitivity after injury in mice (Seal et al. 2009).
In a recent pilot study we found that innocuous tactile stimulation (vibration) of hairy skin intensified the underlying muscle pain (allodynia), and that this effect appeared to be dependent upon cutaneous mechanoreceptors as the allodynia was abolished by intradermal anaesthesia (Nagi et al. 2009).
The ambiguity in the literature about the contribution of different fibre classes to allodynia may be attributed in part to the use of a single-compartment model in which innocuous and noxious stimuli are applied to the same or adjacent regions of skin. Such an approach can lead to uncertainty as to whether any change in pain perception reflects peripheral sensitization of nociceptive fibres and/or an altered central convergence of innocuous and noxious inputs.
The muscle is physically separated from the skin by sheet-like fascia and each is supplied by separate vascular and nerve supplies (O’Rahilly & Muller, 1986; Berry et al. 1995;Salmons, 1995; Gibson et al. 2009). Within the hairy skin it is known that such low-amplitude vibratory stimuli are preferentially encoded by hair follicle afferents at low frequencies (~5 Hz to 100 Hz) and by Pacinian corpuscle receptors at high frequencies (~50 Hz to 1000 Hz: Merzenich & Harrington, 1969; Mahns et al. 2006). Although the response properties of CT fibres to vibratory stimulation remain untested, low-threshold mechanical sensitivity has been demonstrated using soft brushing (Vallbo et al. 1999; Olausson et al. 2002;Loken et al. 2009).
We have shown that innocuous cutaneous vibration can increase the intensity of underlying muscle pain, induced by intramuscular infusion of hypertonic saline, and that this effect (i) persists during compression blockade of myelinated fibres but (ii) is abolished by selective anaesthesia of unmyelinated cutaneous afferents. Thus, vibration-evoked allodynia is evidently dependent upon intact C fibre inputs from the skin, and that these C-fibres have a low mechanical threshold (they responded to 200 μm vibration).
Vibration was described as non-painful by all subjects prior to the induction, and following cessation, of muscle pain. Our observations clearly implicate the mechanically sensitive C-tactile (CT) fibres in mediating this vibration-evoked allodynia. In contrast to earlier work, our psychophysical data indicate that the mechanical sensitivity of CT fibres need not be limited to slowly moving stimuli, as allodynia was evoked by vibration following blockade of myelinated afferents.
Using the same data presented by Loken et al.(2009) an alternative explanation can be advanced, namely that C-fibre and large-diameter afferents are activated in parallel during brush stroking, with a sense of pleasantness emerging when large-diameter responsiveness exceeds that of C-fibres.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia. The use of differential nerve blocks to avoid the co-activation of multiple fibre classes during tactile stimulation – an ambiguity that has plagued earlier studies – confirms the role of CT fibres in mediating allodynia. Hence, it is the complement of active sensory fibres, rather than the activation of a single class of afferents, which determines the perceptual outcome of activating CT fibres. 
 
Neuroimaging studies have shown differential representation of pleasant and painful tactile stimuli in certain areas of the brain involved in emotional processing (insular, orbitofrontal and anterior cingulate cortices: Olausson et al. 2002; Rolls et al. 2003). However, cortical activation evoked by a neutral tactile stimulus predominantly activates the discriminative-cognitive areas, the primary and secondary somatosensory cortices.
The qualia of touch may have evolved mainly in a social context to create a useful construct of the world, e.g. to predict whether the intent behind another’s action was benign or sinister; synthesized with the sense of ‘self’, these inputs subserve reflective self-awareness that characterizes humans as immensely social creatures (Ramachandran, 2004).
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tested my vitamin D level. What do my results mean?

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Om d-vti nivåer og hvor mye man må spise daglig for å komme opp i ønsket verdi. 60 ng/ml x 2,5 = 150 nmol/L

http://www.vitamindcouncil.org/further-topics/i-tested-my-vitamin-d-level-what-do-my-results-mean/

To achieve this level… Take this much supplement per day…
20 ng/ml 1000 IU
30 ng/ml 2200 IU
40 ng/ml 3600 IU
50 ng/ml 5300 IU
60 ng/ml 7400 IU
70 ng/ml 10100 IU
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C-tactile fibers contribute to cutaneous allodynia after eccentric exercise.

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Mer om huden og c-fibre i relasjon til smerte. Denne viser at ved stølhet så forsvinner smerten om man bedøver huden. Så selv om smerten oppleves som at den sitter i hele muskelen, så er det nervene helt ytterst i huden som faktisk responderer i smerteopplevelsen.

http://www.ncbi.nlm.nih.gov/pubmed/23562300

In DOMS state, there was no resting pain, but vibration reproducibly evoked pain (allodynia). The blockade of cutaneous C fibers abolished this effect, whereas it persisted during blockade of myelinated fibers. In the clinical subject, without exposure to eccentric exercise, vibration (and brushing) produced a cognate expression of CT-mediated allodynia. These observations attest to a broader role of CTs in pain processing.

This is the first study to demonstrate the contribution of CT fibers to mechanical allodynia in exercise-induced as well as pathological pain states. These findings are of clinical significance, given the crippling effect of sensory impairments on the performance of competing athletes and patients with chronic pain and neurological disorders.

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An investigation into the peripheral substrates involved in the tactile modulation of cutaneous pain with emphasis on the C-tactile fibres.

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Om hvordan hudens c-fibre spiller inn i smerte.

http://www.ncbi.nlm.nih.gov/pubmed/23604625 (kun abstract)

During cutaneous pain, vibration evoked a significant and reproducible increase in the overall pain intensity (allodynia). The blockade of myelinated fibres abolished the vibration sense, but the vibration-evoked allodynia persisted. Conversely, the blockade of unmyelinated cutaneous fibres abolished the allodynia (while the myelinated fibres were conducting or not). On the basis of these findings, in addition to our earlier work, we conclude that the allodynic effect of CT-fibre activation is not limited to nociceptive input arising from the muscle, but can be equally realized when pain originates in the skin. These results denote a broader role of CTs in pain modulation.

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Tactile sensibility in the human hand: relative and absolute densities of four types of mechanoreceptive units in glabrous skin.

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Nevner tetthet på sensoriske nerver i huden.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1281571/

1. Single unit impulses were recorded with percutaneously inserted tungsten needle electrodes from the median nerve in conscious human subjects.
2. A sample of 334 low threshold mechanoreceptive units innervating the glabrous skin area of the hand were studied. In accordance with earlier investigations, the units were separated into four groups on the basis of their adaptation and receptive field properties: RA, PC, SA I and SA II units.
3. The locations of the receptive fields of individual units were determined and the relative unit densities within various skin regions were calculated. The over-all density was found to increase in the proximo-distal direction. There was a slight increase from the palm to the main part of the finger and an abrupt increase from the main part of the finger to the finger tip. The relative densities in these three regions were 1, 1.6, 4.2.
4. The differences in over-all density were essentially accounted for by the two types of units characterized by small and well defined receptive fields, the RA and SA I units, whereas the PC and SA II units were almost evenly distributed over the whole glabrous skin area.
5. The spatial distribution of densities supports the idea that the RA and SA I units account for spatial acuity in psychophysical tests. This capacity is known to increase in distal direction along the hand.
6. On the basis of histological data regarding the number of myelinated fibres in the median nerve, a model of the absolute unit density was proposed. It was estimated that the density of low threshold mechanoreceptive units at the finger tip is as high as 241 u./cm2, whereas in the palm it is only 58 u./cm2.