Trigger point dry needling as an adjunct treatment for a patient with adhesive capsulitis of the shoulder.

Nevner at dry needling gir en raskere smertereduksjon og bevegelsesøkning ved frozen shoulder. 10 behandlinger ble gjort i dette tilfelle.



Prognosis for adhesive capsulitis has been described as self-limiting and can persist for 1 to 3 years. Conservative treatment that includes physical therapy is commonly advised.


The patient was a 54-year-old woman with primary symptoms of shoulder pain and loss of motion consistent with adhesive capsulitis. Manual physical therapy intervention initially consisted of joint mobilizations of the shoulder region and thrust manipulation of the cervicothoracic region. Although manual techniques seemed to result in some early functional improvement, continued progression was limited by pain. Subsequent examination identified trigger points in the upper trapezius, levator scapula, deltoid, and infraspinatus muscles, which were treated with dry needling to decrease pain and allow for higher grades of manual intervention.


The patient was treated for a total of 13 visits over a 6-week period. After trigger point dry needling was introduced on the third visit, improvements in pain-free shoulder range of motion and functional outcome measures, assessed with the Shoulder Pain and Disability Index and the shortened form of the Disabilities of the Arm, Shoulder and Hand questionnaire, exceeded the minimal clinically important difference after 2 treatment sessions. At discharge, the patient had achieved significant improvements inshoulder range of motion in all planes, and outcome measures were significantly improved.


This case report describes the clinical reasoning behind the use of trigger point dry needlingin the treatment of a patient with adhesive capsulitis. The rapid improvement seen in this patient following the initiation of dry needling to the upper trapezius, levator scapula, deltoid, and infraspinatus muscles suggests that surrounding muscles may be a significant source of pain in this condition.

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.

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.


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)

Neurobiologic basis of craving for carbohydrates.

Denne studen nevner 5 systemer som bidrar til at vi føler behov for karbohydrater. Den viktigste er at serotonin øker i hjernen, noe som over tid kan gi en avhengighet. De nevner også at evnen til å skille sult fra andre interne følelser kan bli dårligere, og at det gir behov for mat når andre ting i kropp og sinn er i ulage.

Serotonergic:  Increased brain serotonin improves mood. Brain serotonin levels depend on the availability of its Trp precursor. Dietary carbohydrates increase the passage of Trp through the blood–brain barrier, unlike proteins, which alter LNAA.  Faced with anxiety, an individual eats carbohydrates, which increase brain serotonin, thus improving mood.

Palatability and hedonic response: The pleasurable experience of eating food with high palatability immediately improves mood. This occurs in individuals with greater genetic sensitivity to sweet taste through the activation of the endogenous opioid system. Faced with anxiety, an individual eats a food with high palatability, activating the hedonic mechanism, which improvesmood.

Motivational system:  Carbohydrates act in the motivational system in the same manner as abused substances. This increases dopamine and endogenous opioids, which are associated with a known pleasurable effect, improving mood. If this behavior is repeated over time, structural changes in the brain are produced that generate dependence on highly palatable foods.

Stress response: Faced with anxiety associated with stress, the HPA axis activates. Highly palatable foods activate the motivational system and reduce the HPA axis, thus regulating the stress system. Therefore, when faced with anxiety, highly palatable food produces a hedonic reward as well as reducing the state of anxiety.

Gene–environment:  Eating is a coping tool to relieve negative emotions. The behavior is learned through inadequate parenting and environment. It also stems from an inability to distinguish hunger from other aversive internal states. There is greater susceptibility in carriers of the A1 allele of the DRD2 dopamine receptor and carriers of the short allele of the serotonin transporter gene.

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.

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.

Diaphragmatic Breathing Reduces Exercise-Induced Oxidative Stress

Om hvordan diafragmisk pust (med magen) øker antioksidantbeskyttelsen og restitusjonen ved å senke kortison og øke melatonin. Gjort på et 24t sykkerlritt hvor de som gjorde 1t pusteing før de sovnet fikk raskere restitusjon. Nevner direkte sammenheng mellom kortisol og melatonin. Og påstår at pusten bør implementeres i ethvert treningsregime som restitusjon.

Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant

Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.

Stress is defined as a physiological reaction to undesired emotional or physical situations. Initially, stress induces an acute response (fight or flight) that is mediated by catecholamines. When stress becomes chronic and lasts for a long time, the stressed organism reacts with physiological alterations to adapt to the unfavorable conditions. This ACTH-mediated reaction affects the immune and neuroendocrine systems, and it is responsible for several diseases [1]. Numerous data support the hypothesis that the pathophysiology of chronic stress can be due, at least partially, to an increase in oxidative stress [24], which may also contributes to heart disease [5,6], rheumatoid arthritis [7,8], hypertension [9,10], Alzheimer’s disease [11,12], Parkinson’s disease [13], atherosclerosis [14] and, finally, aging [15].

High levels of glucocorticoids are known to decrease blood reduced glutathione (GSH) and erythrocyte superoxide dismutase (SOD) activity in rats [20]. Other enzymes are also involved, and NADPH oxidase, xanthine oxidase and uncoupled endothelial nitric oxide synthase are important sources of reactive oxygen species (ROS) in glucocorticoid-induced oxidative stress (see [9] for a review on this argument).

Hormonal reactions to stressors, in particular plasma cortisol levels, are lower in people who meditate than in people who do not [3136], suggesting that it is possible to modulate the neuroendocrine system through neurological pathways. Analysis of oxidative stress levels in people who meditate indicated that transcendental meditation, Zen meditation and Yoga correlate with lower oxidative stress levels [3743].

Melatonin could also be involved in the reduction of oxidative stress because increased levels of this hormone have been reported after meditation [4446]. This neurohormone is considered a strong antioxidant and is used as a treatment for aging. Melatonin in fact, increases several intracellular enzymatic antioxidant enzymes, such as SOD and glutathione peroxidase (GSH-Px) [47,48], and induces the activity of γ-glutamylcysteine synthetase, thereby stimulating the production of the intracellular antioxidant GSH (49]. A number of studies have shown that melatonin is significantly better than the classic antioxidants in resisting free-radical-based molecular destruction. In these in vivostudies, melatonin was more effective than vitamin E, β-carotene [5052] and vitamin C [5355].

Although it has been established that a continuous and moderate physical activity reduces stress, intense and prolonged exercise is deleterious and needs a proper recovery procedure.

Plasma cortisol levels increase in response to intense and prolonged exercise [60,61]. Ponjee et al. [62] demonstrated that cortisol increased significantly in male athletes after they ran a marathon. In another study, plasma ACTH and cortisol were found elevated in highly trained runners and in sedentary subjects after intense treadmill exercise [63].

Most, if not all, meditation procedures involve diaphragmatic breathing (DB), which is the act of breathing deeply into the lungs by flexing the diaphragm rather than the rib cage. DB is relaxing and therapeutic, reduces stress and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices.

Athletes were monitored during a training session for a 24-h long contest. This type of race lasts for 24h, generally starting at 10:00am and ending at 10:00am the following day. Bikers ride as many kilometers as possible on a specific circuit trail in the 24-h period. Athletes are allowed to stop, to sleep, to rest and to eat as much food as they want to eat.

Subjects of the studied group were previously trained to relax by performing DB and concentrating on their breath. These athletes spent 1h (6:30–7:30pm) relaxing performing DB in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. The only activity allowed was reading magazines. Lighting levels were monitored throughout the experiment and did not exceed 15 lux, a level well below that known to influence melatonin secretion [73,74].

As expected, the exercise induced a strong oxidative stress in athletes (Figure 1).

BAP (Biological Antioxidant Potential) levels were determined at different times, before and after exercise. Athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1h relaxing performing DB and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Since this test must be performed several hours after food ingestion, BAP levels were determined pre-exercise at 8:00am before breakfast, at 2:00am, and at 8:00am 24h post-exercise. Values shown are mean ± SD. *P < .05 DB versus control group. **P < .01 DB versus control group.

This study demonstrates that DB reduces the oxidative stress induced by exhaustive exercise. To our knowledge, this is the first study which explores the effect of DB on the stress caused by exhaustive physical activity.

The rationale is as follows (Figure 5)

  1. intense exercise increases cortisol production;
  2. a high plasmatic level of cortisol decreases body antioxidant defenses;
  3. a high plasmatic level of cortisol correlates with a high level of oxidative stress;
  4. DB reduces the production of cortisol;
  5. DB increases melatonin levels;
  6. melatonin is a strong antioxidant;
  7. DB increases the BAP and
  8. DB reduces oxidative stress.

If these results are confirmed in other intense physical activity programs, relaxation could be considered an effective practice to significantly contrast the free radical-mediated oxidative damage induced by intense exercise. Therefore, similar to the way that antioxidant supplementation has been integrated into athletic training programs, DB or other meditation techniques should be integrated into many sports as a method to improve performance and to accelerate recovery.

Hyperventilation, in fact, induces hyperoxia which is known to be related with oxidative stress [81,82]. The hyperventilation syndrome affects 15% of the population and occurs when breathing rates elevate to 21–23 bpm as a result of constricted non-DB. DB can treat hyperoxia and its consequences acting by two synergic ways: restoring the normal breath rhythm and reducing oxidative stress mainly through the increase in melatonin production which is known for its ability to reduce oxidative stress induced by exposure to hyperbaric hyperoxia [83].

Moreover, Orme-Johnson observed greatly reduced pathology levels in regular meditation practitioners [84,85]. A 5 years statistic of approximately 2000 regular participants demonstrated that Transcendental Meditation reduced benign and malignant tumors, heart disease, infectious diseases, mental disorders and diseases of the nervous system. Mourya et al. evidenced that slow-breathing exercises may influence autonomic functions reducing blood pressure in patients with essential hypertension [86]. Finally, there are also evidences that procedures which involve the control of the breathing can positively affect type 2 Diabetes [87], depression, pain [88], high glucose level and high cholesterol [89].

The role of melatonin must also be emphasized. Beyond its antioxidant properties, melatonin is involved in the regulation of the circadian sleep-wake rhythm and in the modulation of hormones and the immune system. Due to its wide medical implications, the increase in melatonin levels induced by DB suggests that this breath procedure deserves to be included in public health improvement programs.

DB increased the levels of melatonin in athletes, and this correlates with lower oxidative stress (ROMs), with lower cortisol levels and with the higher antioxidant status (BAP) in these athletes.

Tooley et al. [46] speculated that meditation-reduced hepatic blood flow [91] could raise the plasma levels of melatonin. Alternatively, since meditation increases plasma levels of noradrenaline [92] and urine levels of the metabolite 5HIAA [93], a possible direct action on the pineal gland could be hypothesized, as melatonin is synthesized in the pineal by serotonin under a noradrenaline stimulus [94]. More likely, we suspect that the increase in melatonin levels determined in our experiment can be mainly attributed to the reduced cortisol levels. Actually, a relationship between cortisol and melatonin rhythms has been observed [95], indicating that melatonin onset typically occurs during low cortisol secretion.

Overall, these data demonstrate that relaxation induced by DB increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol, which is known to negatively affect antioxidant defenses, and the increase in melatonin, a strong antioxidant. The consequence is a lower level of oxidative stress, which suggests that an appropriate recovery could protect athletes from long-term adverse effects of free radicals.


Svært viktig studie med alt om smerte, fra Melzaks Body-Self Neuromatrix. Smerteforståelsens historie, fantomsmerter, hypersensitivitet, nervedegenerasjon, betennelser, Gate Control og Neuromatrix teori, m.m. Her forklares hvordan kroppsopplevelsen skapes i hjernen, selv uten noen input fra kroppen. Nevner også at smerte kan sette seg som et minne; somatic memory. Og vier mye plass til hvordan stress og kortisol bidrar til kroniske smerter, muskelsvikt og nedsatt immunsystem.

Smerte har en funksjon i menneskekroppen som har utviklet seg i evolusjonen for å holde oss i live. Det gjør at vi tilpasser vår aktivitet så kroppen kan fokusere på helbredelse.

Pain has many valuable functions. It often signals injury or disease, generates a wide range of adaptive behaviors, and promotes healing through rest.

Men de siste 100-årenes (og foreløpige) forståelse av selve årsaken til smerte, hvordan den oppstår og hvordan den forsvinner, er basert på et mekanisk kroppsbilde som ikke tar hensyn til den subjektive smerteopplevelse. Melsaks arbeid viser oss hvordan vi snur dette og får en bedre og mer korrekt forståelse av smertefunksjonen:

Pain is a personal, subjective experience influenced by cultural learning, the meaning of the situation, attention, and other psychological variables. Pain processes do not begin with the stimulation of receptors. Rather, injury or disease produces neural signals that enter an active nervous system that (in the adult organism) is the substrate of past experience, culture, and a host of other environmental and personal factors.

Pain is not simply the end product of a linear sensory transmission system; it is a dynamic process that involves continuous interactions among complex ascending and descending systems. The neuromatrix theory guides us away from the Cartesian concept of pain as a sensation produced by injury, inflammation, or other tissue pathology and toward the concept of pain as a multidimensional experience produced by multiple influences.

Smerte er en helbredelsesfunksjon. Den hjelper oss å unngå truende situasjoner og sørger for at vi gir kroppen mulighet til å helbrede seg. Det er en naturlig og intelligent biologisk funksjon som i milliarder av år igjennom evolusjonen har sørget for at vi overlever så lenge som mulig.

We all know that pain has many valuable functions. It often signals injury or disease and generates a wide range of behaviors to end it and to treat its causes. Chest pain, for example, may be a symptom of heart disease, and may compel us to seek a physician’s help. Memories of past pain and suffering also serve as signals for us to avoid potentially dangerous situations. Yet another beneficial effect of pain, notably after serious injury or disease, is to make us rest, thereby promoting the body’s healing processes. All of these actions induced by pain—to escape, avoid, or rest—have obvious value for survival.

Smerteproblematikk har eksplodert de siste 20-30 årene og korsryggsmerter har overtatt plassen fra sult som den viktigste årsaken til ubehag blandt verdens befolkning. Melzak foreslår at vi bør se på kronisk smerte som en sykdom i seg selv, ikke som et symptom. En sykdom som følge av at nervesystemets alarm-mekanismer har slått seg vrang.

The pain, not the physical impairment, prevents them from leading a normal life. Likewise, most backaches, headaches, muscle pains, nerve pains, pelvic pains, and facial pains serve no discernible purpose, are resistant to treatment, and are a catastrophe for the people who are afflicted.

Pain may be the warning signal that saves the lives of some people, but it destroys the lives of countless others. Chronic pains, clearly, are not a warning to prevent physical injury or disease. They are the disease—the result of neural mechanisms gone awry.1–3


I smerteforskning og forståelse har vi, siden Descartes tid på 1600-tallet, beveget oss fra utsiden av kroppen igjennom det vi trodde var smerte-nervetråder, inn til ryggmargens «Gate Control», og nå, med The Neuromatrix, kommet opp til selve hjernen hvor vår opplevde virkelighet faktisk skapes. Først nå de siste årene har vi begynt å inkludere hjernens forskjellige funksjoner og dens eget «bilde» og opplevelse av kroppen. Tidligere ville pasienter som ikke ble bedre av kirurgi eller behandling bare bli avfeid av legene og heller sent til psykolog, hvor de heller ikke fikk noe spesifikk hjelp for smertene. Først nå, endelig, kan behandling av kronisk smerte inkludere større deler av mennesket som stemmer bedre overens med realiteten i både den subjektive opplevelsen og den vitenskapelige forklaringsmodellen.

The theory of pain we inherited in the 20th century was proposed by Descartes three centuries earlier. The impact of Descartes’ specificity theory was enormous. It influenced experiments on the anatomy and physiology of pain up to the first half of the 20th century (reviewed in Ref 4). This body of research is marked by a search for specific pain fibers and pathways and a pain center in the brain. The result was a concept of pain as a specific, direct-line sensory projection system. This rigid anatomy of pain in the 1950s led to attempts to treat severe chronic pain by a variety of neurosurgical lesions. Descartes’ specificity theory, then, determined the ‘facts’ as they were known up to the middle of the 20th century, and even determined therapy.

Specificity theory proposed that injury activates specific pain receptors and fibers which, in turn, project pain impulses through a spinal pain pathway to a pain center in the brain. The psychological experience of pain, therefore, was virtually equated with peripheral injury. In the 1950s, there was no room for psychological contributions to pain, such as attention, past experience, anxiety, depression, and the meaning of the situation.

Patients who suffered back pain without presenting signs of organic disease were often labeled as psychologically disturbed and sent to psychiatrists. 

However, in none of these theories was there an explicit role for the brain other than as a passive receiver of messages. Nevertheless, the successive theoretical concepts moved the field in the right direction: into the spinal cord and away from the periphery as the exclusive answer to pain. At least the field of pain was making its way up toward the brain.


(D) Gate control theory. The large (L) and small (S) fibers project to the substantia gelatinosa (SG) and first central transmission (T) cells. The central control trigger is represented by a line running from the large fiber system to central control mechanisms, which in turn project back to the gate control system. The T cells project to the entry cells of the action system. +, excitation; −, inhibition.


The Gate Control beskriver hvordan stimulering av store nervefibre, f.eks. å blåse på sår, stryke på huden, osv., (mekanoreseptorer i huden) kan overdøve smertesignalene som kommer fra små nervefibre (nociceptive C-fibre). Gate Control teorien var den første som viste hvordan sentralnervesystemet kunne nedregulere smerte ovenifra og ned. Som inkluderer hjernens respons på signalene fra kroppen.

The final model, depicted in Figure 1(d), is the first theory of pain to incorporate the central control processes of the brain.

The gate control theory of pain11 proposed that the transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a gating mechanism in the spinal dorsal horn. This gating mechanism is influenced by the relative amount of activity in large- and small-diameter fibers, so that large fibers tend to inhibit transmission (close the gate) while small-fibers tend to facilitate transmission (open the gate).

When the output of the spinal T cells exceeds a critical level, it activates the Action System—those neural areas that underlie the complex, sequential patterns of behavior and experience characteristic of pain.

Psychological factors, which were previously dismissed as ‘reactions to pain’, were now seen to be an integral part of pain processing and new avenues for pain control by psychological therapies were opened.


We believe the great challenge ahead of us is to understand brain function. Melzack and Casey13 made a start by proposing that specialized systems in the brain are involved in the sensory-discriminative, motivational-affective and cognitive-evaluative dimensions of subjective pain experience (Figure 2).


Figure 2. Conceptual model of the sensory, motivational, and central control determinants of pain. The output of the T (transmission) cells of the gate control system projects to the sensory-discriminative system and the motivational-affective system. The central control trigger is represented by a line running from the large fiber system to central control processes; these, in turn, project back to the gate control system, and to the sensory-discriminative and motivational-affective systems. All three systems interact with one another, and project to the motor system.

The newest version, the Short-Form McGill Pain Questionnaire-2,16 was designed to measure the qualities of both neuropathic and non-neuropathic pain in research and clinical settings.

In 1978, Melzack and Loeser17 described severe pains in the phantom body of paraplegic patients with verified total sections of the spinal cord, and proposed a central ‘pattern generating mechanism’ above the level of the section. This concept represented a revolutionary advance: it did not merely extend the gate; it said that pain could be generated by brain mechanisms in paraplegic patients in the absence of a spinal gate because the brain is completely disconnected from the cord. Psychophysical specificity, in such a concept, makes no sense; instead we must explore how patterns of nerve impulses generated in the brain can give rise to somesthetic experience.

Phantom Limbs and the Concept of a Neuromatrix

But there is a set of observations on pain in paraplegic patients that just does not fit the theory. This does not negate the gate theory, of course. Peripheral and spinal processes are obviously an important part of pain and we need to know more about the mechanisms of peripheral inflammation, spinal modulation, midbrain descending control, and so forth. But the data on painful phantoms below the level of total spinal cord section18,19 indicate that we need to go above the spinal cord and into the brain.

The cortex, Gybels and Tasker made amply clear, is not the pain center and neither is the thalamus.20 The areas of the brain involved in pain experience and behavior must include somatosensory projections as well as the limbic system.

First, because the phantom limb feels so real, it is reasonable to conclude that the body we normally feel is subserved by the same neural processes in the brain as the phantom; these brain processes are normally activated and modulated by inputs from the body but they can act in the absence of any inputs.

Second, all the qualities of experience we normally feel from the body, including pain, are also felt in the absence of inputs from the body; from this we may conclude that the origins of the patterns of experience lie in neural networks in the brain; stimuli may trigger the patterns but do not produce them.

Third, the body is perceived as a unity and is identified as the ‘self’, distinct from other people and the surrounding world. The experience of a unity of such diverse feelings, including the self as the point of orientation in the surrounding environment, is produced by central neural processes and cannot derive from the peripheral nervous system or spinal cord.

Fourth, the brain processes that underlie the body-self are ‘built-in’ by genetic specification, although this built-in substrate must, of course, be modified by experience, including social learning and cultural influences. These conclusions provide the basis of the conceptual model18,19,21 depicted in Figure 3.


Figure 3. Factors that contribute to the patterns of activity generated by the body-self neuromatrix, which is comprised of sensory, affective, and cognitive neuromodules. The output patterns from the neuromatrix produce the multiple dimensions of pain experience, as well as concurrent homeostatic and behavioral responses.

Outline of the Theory

The anatomical substrate of the body-self is a large, widespread network of neurons that consists of loops between the thalamus and cortex as well as between the cortex and limbic system.18,19,21 The entire network, whose spatial distribution and synaptic links are initially determined genetically and are later sculpted by sensory inputs, is a neuromatrix. The loops diverge to permit parallel processing in different components of the neuromatrix and converge repeatedly to permit interactions between the output products of processing. The repeated cyclical processing and synthesis of nerve impulses through the neuromatrix imparts a characteristic pattern: the neurosignature. The neurosignature of the neuromatrix is imparted on all nerve impulse patterns that flow through it; the neurosignature is produced by the patterns of synaptic connections in the entire neuromatrix.

The neurosignature, which is a continuous output from the body-self neuromatrix, is projected to areas in the brain—the sentient neural hub—in which the stream of nerve impulses (the neurosignature modulated by ongoing inputs) is converted into a continually changing stream of awareness. Furthermore, the neurosignature patterns may also activate a second neuromatrix to produce movement, the action-neuromatrix .

The Body-Self Neuromatrix

The neuromatrix (not the stimulus, peripheral nerves or ‘brain center’) is the origin of the neurosignature; the neurosignature originates and takes form in the neuromatrix. Though the neurosignature may be activated or modulated by input, the input is only a ‘trigger’ and does not produce the neurosignature itself. The neuromatrix ‘casts’ its distinctive signature on all inputs (nerve impulse patterns) which flow through it.

The neuromatrix, distributed throughout many areas of the brain, comprises a widespread network of neurons which generates patterns, processes information that flows through it, and ultimately produces the pattern that is felt as a whole body.

Conceptual Reasons for a Neuromatrix

It is difficult to comprehend how individual bits of information from skin, joints, or muscles can all come together to produce the experience of a coherent, articulated body. At any instant in time, millions of nerve impulses arrive at the brain from all the body’s sensory systems, including the proprioceptive and vestibular systems. How can all this be integrated in a constantly changing unity of experience? Where does it all come together?

The neuromatrix, then, is a template of the whole, which provides the characteristic neural pattern for the whole body (the body’s neurosignature) as well as subsets of signature patterns (from neuromodules) that relate to events at (or in) different parts of the body

Alle har sett filmen The Matrix, sant? Spesielt scenen med «the spoonboy» er magisk: «Do not try to bend the spoon. That is impossible. Instead… only try to realize the truth» Neo: «What truth?». Spoonboy: «There is no spoon». Neo: «There is no spoon?». Spoonboy: «Then you´ll see, that it is not the spoon that bends, it is only your self». Dette har en direkte relasjon til smerteopplevelsen. Melzack forklarer:

Pain is not injury; the quality of pain experiences must not be confused with the physical event of breaking skin or bone. Warmth and cold are not ‘out there’; temperature changes occur ‘out there’, but the qualities of experience must be generated by structures in the brain. There are no external equivalents to stinging, smarting, tickling, itch; the qualities are produced by built-in neuromodules whose neurosignatures innately produce the qualities.

We do not learn to feel qualities of experience: our brains are built to produce them.

When all sensory systems are intact, inputs modulate the continuous neuromatrix output to produce the wide variety of experiences we feel. We may feel position, warmth, and several kinds of pain and pressure all at once. It is a single unitary feeling just as an orchestra produces a single unitary sound at any moment even though the sound comprises violins, cellos, horns, and so forth.

The experience of the body-self involves multiple dimensions—sensory, affective, evaluative, postural and many others.

To use a musical analogy once again, it is like the strings, tympani, woodwinds and brasses of a symphony orchestra which each comprise a part of the whole; each makes its unique contribution yet is an integral part of a single symphony which varies continually from beginning to end.

Action Patterns: The Action-Neuromatrix

The output of the body neuromatrix is directed at two systems: (1) the neuromatrix that produces awareness of the output, and (2) a neuromatrix involved in overt action patterns. Just as there is a steady stream of awareness, there is also a steady output of behavior (including movements during sleep).

It is important to recognize that behavior occurs only after the input has been at least partially synthesized and recognized. For example, when we respond to the experience of pain or itch, it is evident that the experience has been synthesized by the body-self neuromatrix (or relevant neuromodules) sufficiently for the neuromatrix to have imparted the neurosignature patterns that underlie the quality of experience, affect and meaning. Most behavior occurs only after inputs have been analyzed and synthesized sufficiently to produce meaningful experience.

When we reach for an apple, the visual input has clearly been synthesized by a neuromatrix so that it has 3-dimensional shape, color and meaning as an edible, desirable object, all of which are produced by the brain and are not in the object ‘out there’. When we respond to pain (by withdrawal or even by telephoning for an ambulance), we respond to an experience that has sensory qualities, affect and meaning as a dangerous (or potentially dangerous) event to the body.

After inputs from the body undergo transformation in the body-neuromatrix, the appropriate action patterns are activated concurrently (or nearly so) with the neuromatrix for experience. Thus, in the action-neuromatrix, cyclical processing and synthesis produces activation of several possible patterns, and their successive elimination, until one particular pattern emerges as the most appropriate for the circumstances at the moment. In this way, input and output are synthesized simultaneously, in parallel, not in series. This permits a smooth, continuous stream of action patterns.

Another entrenched assumption is that perception of one’s body results from sensory inputs that leave a memory in the brain; the total of these signals becomes the body image. But the existence of phantoms in people born without a limb or who have lost a limb at an early age suggests that the neural networks for perceiving the body and its parts are built into the brain.18,19,27,28

Phantoms become comprehensible once we recognize that the brain generates the experience of the body. Sensory inputs merely modulate that experience; they do not directly cause it.

Pain and Neuroplasticity

Plasticity related to pain represents persistent functional changes, or ‘somatic memories,’29–31 produced in the nervous system by injuries or other pathological events.

Denervation Hypersensitivity and Neuronal Hyperactivity

Clinical neurosurgery studies reveal a similar relationship between denervation and CNS hyperactivity. Neurons in the somatosensory thalamus of patients with neuropathic pain display high spontaneous firing rates, abnormal bursting activity, and evoked responses to stimulation of body areas that normally do not activate these neurons.34,35

Furthermore, in patients with neuropathic pain, electrical stimulation of subthalamic, thalamic and capsular regions may evoke pain36 and in some instances even reproduce the patient’s pain.37–39

It is possible that receptive field expansions and spontaneous activity generated in the CNS following peripheral nerve injury are, in part, mediated by alterations in normal inhibitory processes in the dorsal horn. Within four days of a peripheral nerve section there is a reduction in the dorsal root potential, and therefore, in the presynaptic inhibition it represents.40 Nerve section also induces a reduction in the inhibitory effect of A-fiber stimulation on activity in dorsal horn neurons.41

The fact that amputees are more likely to develop phantom limb pain if there is pain in the limb prior to amputation30 raises the possibility that the development of longer term neuropathic pain also can be prevented by reducing the potential for central sensitization at the time of amputation.52,53

Pain and Psychopathology

Pain that is ‘nonanatomical’ in distribution, spread of pain to non-injured territory, pain that is said to be out of proportion to the degree of injury, and pain in the absence of injury have all, at one time or another, been used as evidence to support the idea that psychological disturbance underlies the pain. Yet each of these features of supposed psychopathology can now be explained by neurophysiological mechanisms that involve an interplay between peripheral and central neural activity.4,60

This raises the intriguing possibility that the intensity of pain at the site of an injury may be facilitated by contralateral neurite loss induced by the ipsilateral injury68—a situation that most clinicians would never have imagined possible.

Taken together, these novel mechanisms that explain some of the most puzzling pain symptoms must keep us mindful that emotional distress and psychological disturbance in our patients are not at the root of the pain. In fact, more often than not, prolonged pain is the cause of distress, anxiety, and depression.

Attributing pain to a psychological disturbance is damaging to the patient and provider alike; it poisons the patient-provider relationship by introducing an element of mutual distrust and implicit (and at times, explicit) blame. It is devastating to the patient who feels at fault, disbelieved and alone.

Pain and Stress

We are so accustomed to considering pain as a purely sensory phenomenon that we have ignored the obvious fact that injury does not merely produce pain; it also disrupts the brain’s homeostatic regulation systems, thereby producing ‘stress’ and initiating complex programs to reinstate homeostasis. By recognizing the role of the stress system in pain processes, we discover that the scope of the puzzle of pain is vastly expanded and new pieces of the puzzle provide valuable clues in our quest to understand chronic pain.69

However, it is important for the purpose of understanding pain to keep in mind that stress involves a biological system that is activated by physical injury, infection, or any threat to biological homeostasis, as well as by psychological threat and insult of the body-self.

When injury occurs, sensory information rapidly alerts the brain and begins the complex sequence of events to re-establish homeostasis. Cytokines are released within seconds after injury. These substances, such as gamma-interferon, interleukins 1 and 6, and tumor necrosis factor, enter the bloodstream within 1–4 min and travel to the brain. The cytokines, therefore, are able to activate fibers that send messages to the brain and, concurrently, to breach the blood–brain barrier at specific sites and have an immediate effect on hypothalamic cells. The cytokines together with evaluative information from the brain rapidly begin a sequence of activities aimed at the release and utilization of glucose for necessary actions, such as removal of debris, the repair of tissues, and (sometimes) fever to destroy bacteria and other foreign substances. Following severe injury, the noradrenergic system is activated: epinephrine is released into the blood stream and the powerful locus coeruleus/norepinephrine system in the brainstem projects information upward throughout the brain and downward through the descending efferent sympathetic nervous system. Thus, the whole sympathetic system is activated to produce readiness of the heart, blood vessels, and other viscera for complex programs to reinstate homeostasis.70,71

At the same time, the perception of injury activates the hypothalamic–pituitary–adrenal (HPA) system and the release of cortisol from the adrenal cortex, which inevitably plays a powerful role in determining chronic pain. Cortisol also acts on the immune system and the endogeneous opioid system. Although these opioids are released within minutes, their initial function may be simply to inhibit or modulate the release of cortisol. Experiments with animals suggest that their analgesic effects may not appear until as long as 30 min after injury.

Cortisol is an essential hormone for survival because it is responsible for producing and maintaining high levels of glucose for rapid response after injury or major threat. However, cortisol is potentially a highly destructive substance because, to ensure a high level of glucose, it breaks down the protein in muscle and inhibits the ongoing replacement of calcium in bone. Sustained cortisol release, therefore, can produce myopathy, weakness, fatigue, and decalcification of bone. It can also accelerate neural degeneration of the hippocampus during aging. Furthermore, it suppresses the immune system.

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

Some forms of chronic pain may occur as a result of the cumulative destructive effect of cortisol on muscle, bone, and neural tissue. Furthermore, loss of fibers in the hippocampus due to aging reduces a natural brake on cortisol release which is normally exerted by the hippocampus. As a result, cortisol is released in larger amounts, producing a greater loss of hippocampal fibers and a cascading deleterious effect

The cortisol output by itself may not be sufficient to cause any of these problems, but rather provides the conditions so that other contributing factors may, all together, produce them. 

The fact that several autoimmune diseases are also classified as chronic pain syndromes—such as Crohn’s disease, multiple sclerosis, rheumatoid arthritis, scleroderma, and lupus—suggests that the study of these syndromes in relation to stress effects and chronic pain could be fruitful. Immune suppression, which involves prolonging the presence of dead tissue, invading bacteria, and viruses, could produce a greater output of cytokines, with a consequent increase in cortisol and its destructive effects.

In some instances, pain itself may serve as a traumatic stressor.

Phantom Limb Pain

The cramping pain, however, may be due to messages from the action-neuromodule to move muscles in order to produce movement. In the absence of the limbs, the messages to move the muscles become more frequent and ‘stronger’ in the attempt to move the limb. The end result of the output message may be felt as cramping muscle pain. Shooting pains may have a similar origin, in which action-neuromodules attempt to move the body and send out abnormal patterns that are felt as shooting pain. The origins of these pains, then, lie in the brain.

Low-Back Pain

Protruding discs, arthritis of vertebral joints, tumors, and fractures are known to cause low back pain. However, about 60–70% of patients who suffer severe low back pain show no evidence of disc disease, arthritis, or any other symptoms that can be considered the cause of the pain. Even when there are clear-cut physical and neurological signs of disc herniation (in which the disc pushes out of its space and presses against nerve roots), surgery produces complete relief of back pain and related sciatic pain in only about 60% of cases.

A high proportion of cases of chronic back pain may be due to more subtle causes. The perpetual stresses and strains on the vertebral column (at discs and adjacent structures called facet joints) produce an increase in small blood vessels and fibrous tissue in the area.78 As a result, there is a release of substances that are known to produce inflammation and pain into local tissues and the blood stream; this whole stress cascade may be triggered repeatedly. The effect of stress-produced substances—such as cortisol and norepinephrine—at sites of minor lesions and inflammation could, if it occurs often and is prolonged, activate a neuromatrix program that anticipates increasingly severe damage and attempts to counteract it.


An understanding of fibromyalgia has eluded us because we have failed to recognize the role of stress mechanisms in addition to the obvious sensory manifestations which have dominated research and hypotheses about the nature of fibromyalgia. Melzack’s interpretation of the available evidence is that the body-self neuromatrix’s response to stressful events fails to turn off when the stressor diminishes, so that the neuromatrix maintains a continuous state of alertness to threat. It is possible that this readiness for action produces fatigue in muscles, comparable to the fatigue felt by paraplegics in their phantom legs when they spontaneously make cycling movements.24 It is also possible that the prolonged tension maintained in particular sets of muscles produces the characteristic pattern of tender spots.

The persistent low-level stress (i.e., the failure of the stress response to cease) would produce anomalous alpha waves during deep sleep, greater feelings of fatigue, higher generalized sensitivity to all sensory inputs, and a low-level, sustained output of the stress-regulation system, reflected in a depletion of circulating cortisol.

Pain Sensitivity and Analgesic Effects of Mindful States in Zen Meditators: A Cross-Sectional Study

Nevner hvordan smerteopplevelse blir mindre med meditasjon, men viser også til at det sannsynligvis er pustefrekvensen som gir den smertestillende effekten. Pluss den nevner hvordan frontallappen bidrar med smertestillende opioider.

These results indicated that Zen meditators have lower pain sensitivity and experience analgesic effects during mindful states. Results may reflect cognitive/self-regulatory skills related to the concept of mindfulness and/or altered respiratory patterns.

Mindfulness can be described as an equanimous state of observation of one’s own immediate and ongoing experience.

Mindfulness has been described as “intentional self-regulation of attention from moment to moment … of a constantly changing field of objects … to include, ultimately, all physical and mental events….” (5). Furthermore, an attitude of acceptance toward any and all experience is stressed. Traditional accounts of mental and emotional transformation accompanying mindful practice (6,7) are supported by scientific findings of psychological and biological effects on practitioners (8–10) and patients (5,11–15).

Mindfulness-based therapies have reported success treating anxiety (11,15), obsessive compulsive disorder (13), and depression (12,14). Positive correlations between meditation experience of Buddhist monks and positive affect (10) have been reported. Increases in positive affect have also been observed in a longitudinal study in which naïve subjects were trained to meditate (8).

It is well known that cognitive manipulations, such as hypnosis, attention, expectancy or placebo, can influence the experience of pain and the associated neurophysiological activity (17–19). There is also mounting evidence that mindfulness may be effective in treating chronic pain.

Significant positive improvements were found on all measures immediately after the 10-week training program. However, follow-up evaluation showed stable improvements on most measures with the exception of present moment pain. The authors interpreted the results as the acquisition of an effective coping strategy for pain, where the pain itself did not change but the relation or stance taken toward the pain was positively altered.

Changes in pain were further examined in relationship to meditation training. The amount of meditation experience of individual practitioners predicted the degree of pain intensity modulation (i.e., versus baseline) with more hours of experience leading to greater reductions in pain intensity during the mindfulness condition [r(9) = −.82, p< .01].

Notably, pain modulation induced by mindfulness (relative to baseline-1) was correlated with the corresponding changes in respiratory rate across all subjects [intensity: r(23) = .37, p = .03; unpleasantness: r(23) = .42, p = .02]. Furthermore, the significant decrease in pain intensity reported above in the meditators during the mindfulness condition relative to baseline-1 (Figure 2) did not reach significance after including the changes in respiration as a covariate [F(1,11) = 3.02, p = .11]. In contrast, the significant increase in pain intensity reported by the control subjects in the concentration condition remained significant after accounting for changes in respiratory rates [F(1,11) = 20.94, p = .001]. These effects suggest that the changes in pain induced by mindfulness, but not concentration, may be at least partly accounted for by changes in respiration.

The main findings are the following:

  • 1) Meditators required hotter temperatures than controls to experience moderate pain.
  • 2) As hypothesized, meditators experienced less pain while attending mindfully, whereas control subjects did not show such modulation.
  • 3) Unexpectedly, analgesic effects of mindfulness were more clear on the sensory dimension of pain (i.e., perceived intensity) than the affective dimension of pain (i.e., pain unpleasantness), although effects were observed in the same direction.
  • 4) The magnitude of the analgesic effect of mindfulness was predicted by the number of hours of meditation practice in meditators.
  • 5) When attention was directed toward the stimulation, with no mention of attending mindfully, control subjects showed the expected increase in pain intensity and unpleasantness whereas meditators did not differ from baseline.
  • 6) Physiologically, meditators had slower breathing rates than controls, consistent with their self-assessed reduced reactivity. Importantly, changes in respiratory rate predicted the changes in felt pain and the analgesic effect of mindfulness states was no longer significant after accounting for changes in respiratory rates (covariance).
  • 7) On a mindfulness scale, meditators scored higher on the tendency to be observant and nonreactive. Higher scores on these dimensions of mindfulness were further associated with lower pain sensitivity and slower respiratory rates.

Zen meditation was associated with lower pain sensitivity as demonstrated by the higher temperatures required to produce moderate pain. The observed difference (49.9°C versus 48.2°C) should be considered large as it typically corresponds to an increase of about 50% on a ratio scale of pain perception or 20 to 25 points on a 0 to 100 numerical pain scale, based on similar psychophysical methods (28,33).

While attending mindfully, the Zen practitioners showed reductions of 18% pain intensity. Remarkably, individuals with more extensive training experienced greater reduction in pain. This finding is extremely important as it suggests that the observed pain reduction may not simply reflect a predisposition to meditation (individual differences) but may also involve experience-dependent changes associated with practice. This is in line with other studies linking meditation training with mindfulness, medical symptoms, and well-being (16); attention performance, anxiety, depression, anger, cortisol and immunoreactivity (34); an inverted U-shaped function of attention-related brain activity (35); electrophysiological markers of positive affect (10); positive affect and stronger immune responses (8); and cortical thickness and gray matter density (9,36,37).

The analgesic effects of mindful attention may relate to the physiological state induced as suggested by the respiration data. Overall, the meditators breathed at a slower rate than control subjects in all conditions and their mean respiratory pattern followed that of their pain ratings. In contrast, respiratory rate did not change noticeably across conditions in the control subjects. Slower breathing rates (typically meditators) were associated with less reactivity and with lower pain sensitivity. These relationships suggested that the meditators were in a more relaxed, nonreactive physiological state throughout the study, which culminated in the mindfulness condition and which influenced the degree to which they experienced pain.

The covariance analysis suggested that this analgesic effect could be mediated at least in part by the observed change in respiration.

A neuro-chemical model of meditation put forth by Newberg and Iversen (47) offers a possible explanation for our results. Meditation practice, involving volitional regulation of attention, seems to activate prefrontal cortex (35,48,49); this has been observed during Zen practice (50). Increases in prefrontal activation can stimulate the production of b-endorphin (e.g., in the arcuate nucleus of the hypothalamus) (47). B-endorphin is an opiate associated with both analgesia and a reduction in respiratory rate as well as decreases in fear and increases in joy and euphoria (47). Interestingly, the direction of attention toward breathing and the volitional control of breathing rates are part of many meditative techniques; however, causation can obviously not be inferred from those observations.

Another related possibility is that meditation leads to reductions in stress and stress-related chemicals, such as cortisol which interact with the opiate system. A reduction of cortisol can greatly enhance the binding potential/efficacy of endogenous opioids (27), possibly contributing to a downregulation of nociceptive responses. Studies have reported evidence of reduced cortisol responses in meditators (34,52,53).

The role of corticosteroids in the regulation of vascular tone

Viser til mekanismene for hvordan kortisol (og stress) hemmer blodsirkulasjon og over tid kan gi høyt blodtrykk og mange medfølgende sykdommer. Kortisols effekt på blodkar sammentrekning er først og fremst ved å øke reaksjonen og blodkarcellenes sensitivitet til adrenalin. Men også øke nyrenes tilbakeholdelse av salt.

«In addition, corticosteroids in lesser amounts are essential for the maintenance of peripheral vascular resistance in healthy persons. This review details the proposed mechanisms by which corticosteroids maintain and, in excess, enhance vascular tone.»

«Disease states resulting from excesses of circulating (adreno)corticosteroids include primary hyperaldosteronism, renal artery stenosis, ACTH-secreting tumors, and administration of glucocorticoids for treatment of other diseases. Hypertension is commonly associated with these diseases. »

«Potent vasoconstrictor hormones that have been investigated include α-adrenergic agonists (norepinephrine), angiotensin II, arginine vasopressin, endothelin and thromboxanes.»

«Results from other studies have suggested that corticosteroids act directly on blood vessels in potentiating norepinephrine vasoconstrictor actions. »

«Corticosteroids enhance contractile responses to norepinephrine in humans. For example, Kurland and Freedberg [20]administered increasing doses of norepinephrine intravenously to three patients before and 24 h after initiation of glucocorticoid therapy and observed much greater pressor responses in the presence of corticosteroid than in the absence of corticosteroid. »

«For the most part, glucocorticoids and mineralocorticoids have been reported to enhance the vasoconstrictor actions of angiotensin II.»

Viser til at forskjellige steder i kroppen har forskjellig sensitivitet for kortisol:
«It is possible that differences in responses to corticosteroids in vascular beds in different parts of the body may explain the above-mentioned discrepancies. »

«From the above review, one can see that corticosteroids foster hypertension not only by enhancing renal sodium reabsorption but also by augmenting vascular tone. «