Mechanisms Of Pain Modulation Research Articles

Pathology and Possible Mechanisms of Nervous System Response to Disc Degeneration

Degeneration of the intervertebral disc is clinically considered to be an important source of pain in patients with low-back pain. Disc deterioration and/or degeneration may influence the nervous system by stimulation of nociceptors in the anulus fibrosus, causing nociceptive pain that is often referred to as discogenic pain. The stimulation of the nociceptors may be of mechanical or inflammatory origin. Deterioration of a disc with loss of normal structure and weight-bearing properties may lead to abnormal motions that cause mechanical stimulation. This theory is supported by the fact that patients commonly experience an increase in pain with weight-bearing and certain movements. In addition, an ingrowth of vessels and nerve fibers into deeper layers of the anulus fibrosus has been observed in degenerated discs. A large number of inflammatory and signaling substances, such as tumor necrosis factor and interleukins (interleukin-1beta, interleukin-6, and interleukin-8), may also play a role in the development of back pain. Independent of stimulus of the nociceptors, the pain impulses are conducted through myelinated A delta fibers and unmyelinated C fibers to the dorsal root ganglion and continue by way of the spinothalamic tract to the thalamus and the somatosensory cortex. In response to stimulation of the nociceptors in the disc, the somatosensory system may increase its sensitivity, resulting in a nonfunctional response; that is, normally innocuous stimuli may generate an amplified response (peripheral sensitization). When disc degeneration leads to a disc herniation, the adjacent nervous system structures, such as the nerve roots or the dorsal root ganglion, can be affected, causing neuropathic pain of mechanical or biochemical origin. Disc deterioration also influences other spinal structures, such as facet joints, ligaments, and muscles, which can also become pain generators. Thus, disc degeneration may be responsible for the development of chronic low-back pain without being the actual pain focus. Both nociceptive and neuropathic pain can be modulated at higher centers, both at the spinal and the supraspinal levels (central sensitization). The altered magnitude of perceived pain is often referred to as neural plasticity and is considered to play a critical role in the evolution of chronic pain. Together with the complexity of the nervous system and pain modulation mechanisms, psychological aspects may also play a role in the response of the nervous system in patients with chronic low-back pain caused by disc degeneration.

The DREAM of Pain Relief

Chronic pain has manifested itself as an independent disease. Different molecules acting in nociceptive pathways in the periphery and the nervous system are currently under investigation. Recently the multifunctional protein DREAM (D ownstream Regulatory Element Antagonist Modulator)/calsenilin/KChIP3 has been implicated to play a role in the mechanisms of pain modulation and the hypothesis "No DREAM - No pain" was raised. In addition to the binding to DRE (Downstream Regulatory Element) sequences, DREAM/calsenilin/KChIP3 was shown to interact with presenilin, a protein thought to be a key molecule in Alzheimers disease, and Kv4alpha-subunits assembling potassium channels. DREAM/calsenilin/KChIP3 has been described as a Ca2+-dependent transcriptional repressor, which is targeted to the regulatory DNA sequence of the prodynorphin gene. By actively suppressing gene expression of the endogenous opioid receptor ligand dynorphin, DREAM/calsenilin/KChIP3 is modulating the kappa opioid receptor system, which mediates analgesia. DREAM knockout mice showed elevated levels of dynorphin and consequently displayed attenuated chemical induced and inflammatory pain. The data derived from the DREAM knock-out model led to the identification of a novel target in chronic pain management. In this review we focus on DREAM/calsenilin/KChIP3 and its role in pain relief. Keywords: DREAM, calsenilin, KChIP, Kappa opioid receptor, pain, dynorphin

Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide

Fibromyalgia (FM) is a common chronic pain syndrome with an unknown etiology. Recent years added new information to our understanding of FM pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, hypothalamic-pituitary-adrenal axis hormones, oxidative stress, and mechanisms of pain modulation, central sensitization, and autonomic functions in FM revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of FM. Oxidative stress and nitric oxide may play an important role in FM pathophysiology, however it is still not clear whether oxidative stress abnormalities documented in FM are the cause or the effect. This should encourage further researches evaluating the potential role of oxidative stress and nitric oxide in the pathophysiology of FM and the efficacy of antioxidant treatments (omega-3 and -6 fatty acids, vitamins and others) in double blind and placebo controlled trials. These future researches will enhance our understanding of the complex pathophysiology of this disorder.

Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans

The aim of this study was to investigate the effects of diffuse noxious inhibitory controls (DNICs) on the temporal summation of the nociceptive flexion reflex (RIII reflex) in humans. Recordings were obtained from 36 healthy adults (16 M, 20 F), and the area and temporal summation threshold (TST) of the RIII reflex were measured. The subjective intensity of the painful sensation was rated on an 11-point visual analogue scale (VAS). Neurophysiological and VAS measurements were recorded after activation of DNICs by means of the cold pressor test (CPT), which involved immersing the hand in cold water (2–4 °C). A slight significant lower TST was found in the females versus the males. In all the subjects, the CPT induced a significant TST increase and RIII area reduction compared with the control session. The VAS results paralleled those of the RIII reflex area and TST. During the CPT, a significant difference in the percentage TST increase emerged between females and males, being lower in the former. Similarly, we found a significantly lower percentage reduction of the RIII area in women than in men during the CPT. To summarize, activation of DNICs through the CPT significantly increased the TST of the RIII reflex in healthy subjects. This inhibitory effect was gender-specific. Whereas other findings are based on psychophysical evaluations, the results of this experimental study provide an objective neurophysiological demonstration that DNICs attenuate temporal summation in humans and confirm the presence of significant differences in pain modulation mechanisms between men and women.

Muscle pain during exercise in normotensive african american women: effect of parental hypertension history

The purpose of the present investigation was to determine the influence of parental hypertension history on leg muscle pain ratings during cycling exercise in African American women. Eighteen women (age, 19 ± 2 years) with a positive family history (+PH) of hypertension and 16 (age, 19 ± 1 years) with a negative family history (−PH) underwent maximal exercise and cold pressor testing. Maximal exercise was conducted on a cycle ergometer. Quadriceps muscle pain intensity ratings were obtained each minute during the maximal exercise test by using a category-ratio scale. The hand cold pressor test was used to determine cardiovascular reactivity. Repeated measures analysis of variance showed significantly lower pain ratings during exercise for the +PH group compared to the −PH group. Psychophysical power functions indicated that the +PH participants had significantly lower exponents for pain throughout exercise. Systolic blood pressure reactivity did not significantly predict pain ratings during exercise. Normotensive African American women with +PH of hypertension experienced less muscle pain during exercise compared to normotensive African American women with a −PH of hypertension. The results are consistent with data demonstrating reduced sensitivity to experimental pain stimuli in individuals at risk for developing hypertension and extend them to naturally occurring muscle pain produced by exercise. Perspective African American women, a sedentary group with an elevated risk for developing hypertension and chronic pain, show the same negative relationship between +PH and pain perception as men, suggesting that central nervous system mechanisms of pain modulation are more related to family history than gender. Acute exercise provides an experimental model for manipulating naturally occurring pain in studies concerned with the association between pain and hypertension.

Fisiopatologia da fibromialgia

Fibromyalgia is characterized by chronic widespread pain and the presence of tender points on palpation of specific regions of body surface. There is some agreement in various studies on its concentration during the fifth decade of life, association with female gender, as well as socioeconomic factors like low educational levels, low income and being divorced. Hypothesis of anatomopathologic disorders as fisiopathologic explanations of this syndrome have been discarded, since the morphologic alterations were attributed to sedentary lifestyle. At the moment, the most accepted mechanisms for is fisiopathologic understanding include the misbalance between pain perception and modulation mechanisms of afferent pathways. Elevated levels of substance P in the liquor and reduced concentrations of serotonin and its precursors are evidence in this direction, once substance P is a mediator of pain pathways while serotonin mediates its inhibition. Another justification to the reduced activity of serotonin is the polimorphism of cell receptors to this substance, what may also explain the familial grouping of these patients. Cerebral alterations, rostral to the thalamus, could also be responsible for the elevated perception of environmental stimuli, and the perversion of proprioception, pressure and thermal information into pain. Finally, reductionism is not an explanation for fibromyalgia, and multiple explanations have been proposed and accepted, without the exclusion of each other, including psychosocial factor, which have not been explored in this text.

Psychological, neuropsychological, and medical considerations in assessment and management of pain.

Pain is a common yet challenging problem, particularly following traumatic injuries to the head or neck. It is a complex, multidimensional subjective experience with no clear or objective measures; yet it can have a significantly disabling effect across a wide range of functions. Persisting misconceptions owing to mind-body dualism have hampered advances in its understanding and treatment. In this article, a conceptualization of pain informed by recent research and derived from a more useful biopsychosocial model guides discussion of relevant medical, psychological, and neuropsychological considerations. This pain process model explains chronicity in terms of hyperresponsiveness and dysregulation of inhibitory or excitatory pain modulation mechanisms. Related neurocognitive effects of chronic pain are examined and recommendations for minimizing its confounding effects in neuropsychological evaluations are offered. A biopsychosocial assessment model is presented to guide understanding of the myriad of factors that contribute to chronicity. A brief survey of general classes and samples of the more useful pain assessment instruments is included. Finally, this model offers a rational means of organizing and planning individually tailored pain interventions, and some of the most useful pharmacologic, physical, and behavioral strategies are reviewed.

Profile of spinal and supra-spinal antinociception of (−)-linalool

We previously reported that administration of (−)-linalool, the naturally occurring enantiomer in essential oils, induced a significant reduction in carrageenin-induced oedema and in acetic acid-induced writhing. The latter effect was completely antagonised by the muscarinic receptor antagonist atropine and by the opioid receptor antagonist naloxone. To further characterise the antinociceptive profile of (−)-linalool, we studied its effect in the hot plate and the formalin in tests. In addition, to determine the possible involvement of the cholinergic, opioidergic and dopaminergic systems, we tested the effects of atropine, pirenzepine, a muscarinic M1 receptor antagonist, naloxone, sulpiride, a dopamine D2 receptor antagonist and ( R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH-23390), a dopamine D1 receptor antagonist on (−)-linalool-induced antinociception. Moreover, since K + channels seem to play an important role in the mechanisms of pain modulation, we examined the effect of glibenclamide, an ATP-sensitive K + channel inhibitor on (−)-linalool-induced antinociception. The administration of (−)-linalool (100 and 150 mg/kg, s.c.) increased the reaction time in the hot-plate test. Moreover, (−)-linalool (50 and 100 mg/kg) produced a significant reduction in the early acute phase of the formalin model, but not in the late tonic phase. The highest dose (150 mg/kg) caused a significant antinociceptive effect on both phases. The antinociceptive effects of (−)-linalool were decreased by pre-treatment with atropine, naloxone, sulpiride and glibenclamide but not by pirenzepine and SCH-23390. These results are in agreement with the demonstrated pharmacological properties of linalool, mainly its cholinergic, local anaesthetic activity and its ability to block NMDA receptors. Furthermore, a key role seems to be played by K + channels, whose opening might be the consequence of a stimulation of muscarinic M2, opioid or dopamine D2 receptors.

The challenge of defining brainstem pain modulation circuits

Studies of descending pain modulatory systems during the past 2 decades have focused primarily on the midline pathways, those neurons of the periaqueductal gray (vlPAG) that synaptically activate neurons in the rostral ventromedial medulla (RVM) that, in turn, project to the spinal cord and produce analgesia by inhibition of dorsal horn neurons. 19 Fields HL Basbaum Al Central nervous system mechanisms of pain modulation. in: Textbook of Pain. Churchhill Livingstone, Edinburgh1999: 309-329 Google Scholar , 21 Gebhart GF Randich A Brainstem modulation of nociception. in: Brainstem Mechanisms of Behavior. Wiley and Sons, New York1990: 315-352 Google Scholar , 28 Jones SL Descending control of nociception. in: The Initial Processing of Pain and Its Descending Control: Spinal and Trigeminal Systems. Karger, New York1992: 203-295 Google Scholar More recent evidence shows that activation of these descending modulatory neurons can also facilitate nociceptive transmission in the spinal cord dorsal horn. 17 Fang F Proudfit HK Antinociception produced by microinjection of morphine in the periaqueductal gray is enhanced in the rat foot, but not the tail, by intrathecal injection of alpha 1-adrenoceptor antagonists. Brain Res. 1998; 790: 14-24 Crossref PubMed Scopus (38) Google Scholar , 18 Fields HL Is there a facilitating component to central pain modulation?. APS J. 1992; 1: 139-141 Abstract Full Text PDF Scopus (1) Google Scholar , 43 Urban MO Jiang MC Gebhart GF Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil. Brain Res. 1996; 737: 83-91 Crossref PubMed Scopus (119) Google Scholar , 44 Urban MO Gebhart GF Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci U S A. 1999; 96: 7687-7692 Crossref PubMed Scopus (454) Google Scholar , 54 Zhuo M Gebhart GF Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. J Neurophysiol. 1992; 67: 1599-1614 PubMed Google Scholar The review by Tavares and Lima 42 Tavares I Lima D The caudal ventrolateral medulla as an important inhibitory modulator of pain transmission at the spinal cord. J Pain. 2002; 3: 337-346 Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar presents evidence for an additional system of pain modulatory neurons that originates in the caudal ventrolateral medulla (VLM).

Mechanisms of pain modulation in chronic syndromes.

Transmission of pain from the periphery to the cortex depends on integration and signal processing within the spinal cord, brainstem, and forebrain. Sensitization, a component of persistent or chronic pain, may develop either through peripheral mechanisms or as a consequence of altered physiology in the spinal cord or forebrain. Several molecular and biophysical mechanisms contribute to the phenomenon of sensitization and persistent pain, including upregulation of sensory neuron-specific sodium channels and vanilloid receptors, phenotypic switching of large myelinated axons, sprouting within the dorsal horn, and loss of inhibitory neurons due to apoptotic cell death. Recently, forebrain structures have been implicated in the pathophysiology of persistent pain. Although a number of treatment options are used, unfortunately pharmacotherapy for neuropathic pain is often ineffective. Unraveling the mysteries of chronic pain may lead to better treatment options, such as drugs that act specifically on sensory neuron-specific sodium channels or as NR2B-subunit-selective N-methyl-D-aspartate receptor antagonists.

Group differences in pain modulation: pain-free women compared to pain-free men and to women with TMD

Previously reported differences in sensitivity to experimental pain stimuli between the sexes, as well as between temporomandibular disorder (TMD) patients and healthy control subjects, may be attributable in part to group differences in two pain modulatory mechanisms: the baroreceptor reflex arc and the endogenous opioid system. Twenty-two pain-free (PF) men, 20 PF women and 20 women with TMD underwent two testing sessions in which heat pain and ischemic arm pain threshold and tolerance were measured during both sessions, but followed relaxation during one session and laboratory stress tasks during the other. Blood pressure (BP) and plasma β-endorphin (βE) concentration were measured during a baseline rest and during the stress or relaxation periods. PF men's threshold and tolerance for heat pain, but not for ischemic pain, exceeded that of PF women's during both sessions. PF women and TMD women did not differ in sensitivity to either pain modality; however, significantly lower ischemic pain threshold (IPTh) was linked to oral contraceptive use in PF women but not TMD patients. In the men alone, higher baseline systolic BP (SBP) was correlated with higher heat pain threshold on both days and heat pain tolerance on the stress day. Conversely, in TMD women, higher baseline SBP was correlated with lower ischemic pain tolerance (IPTol) on both days; BP and pain sensitivity were not related in PF women. In men, but not in PF or TMD women, stress systolic and diastolic BP were positively correlated with heat pain threshold and tolerance and higher diastolic reactivity to stress were correlated with higher heat pain and IPTh and tolerance. On the stress day, higher baseline βE level was strongly associated with higher IPTol in PF women but marginally associated with lower IPTol in TMD women. Thus, it appears that a BP-related analgesic mechanism (probably baroreceptor-mediated) predominates in PF men, while an endogenous opioid mechanism predominates in PF women. Stress enhances the expression of these central mechanisms. Female TMDs appear unable to effectively engage normal pain-inhibitory systems; opioid receptor desensitization and/or downregulation are probably implicated, because TMDs' production of βE appears normal.

Smertelindring — Ny kunnskap gir nye muligheter

This paper gives a brief review of the knowledge and research on pain. Later research emphasize the fact that the central nervous system as a whole and especially the brain itself plays a crucial role when it comes to understanding the mechanisms of pain perception and pain modulation. Clinical experience and empirical research on phantom limbs and phantom limb pain lay growing evidence on the assumption that the human brain have build in structures of a neural network which consists of loops that integrate the somatosensory talamus and cortex, the limbic system and the association cortex. This network which is in part genetically determined, is suggested to play a substantial role in integrating and modulating the pain experience. Research further indicate that our body perception is not a passive process merely reflecting bodily input. The pain experience and the feeling of pain quality is not primarily a result of sensory input, but rather generated by our brain together with other bodily experiences. ...

Central mechanisms of pain modulation

Bulbospinal serotonergic neurons and two physiological classes of bulbospinal nonserotonergic cells interact to modulate pain transmission. Recent studies have begun to elaborate targets of descending pain modulation other than the well-studied flexion withdrawal pathways. Site-specific, naloxone-sensitive placebo analgesia, which is hard to reconcile with current models of descending pain modulation, presents an exciting challenge to the field.

Evolving concepts in irritable bowel syndrome

Converging evidence from investigations of the peripheral and central aspects of bidirectional brain-gut interactions is beginning to shape a pathophysiological model of irritable bowel syndrome (IBS) and related functional gastrointestinal (GI) disorders. This neurobiological model includes alterations in autonomic, neuroendocrine, and pain modulatory mechanisms. The frequent association of IBS and other functional GI disorders with co-morbid affective disorders and temporal association of symptom exacerbation with psychosocial or physical stressors are consistent with alterations in the neurobiological mechanisms underlying the central stress response. Renewed interest in drug development for IBS has resulted in development of instruments for the better assessment of the impact of global symptoms on quality of life and in the development of candidate compounds undergoing clinical evaluation.

Antioxidant properties of the triaminopyridine, flupirtine

ABSTRACT. Flupirtine is a triaminopyridine-derived centrally acting analgesic, which interacts with mechanisms of noradrenergic pain modulation. Recently, it has been found to display neuroprotective effects in various models of excitotoxic cell damage, global and focal ischemia. Although this profile suggests that flupirtine acts as an antagonist of the N-methyl- D-aspartate (NMDA) and glutamate-triggered Ca 2+ channel, there is no direct interaction with the receptor. In this paper, we examined whether flupirtine can act as an antioxidant and prevent free radical-mediated structural damage. Flupirtine at 5–30 μM inhibited ascorbate/Fe 2+ (1–10 μM)-stimulated formation of thiobarbituric reactive substances, an indicator of lipid peroxidation, in rat brain mitochondria. Interestingly, we found an increasing effectiveness of the drug at higher iron concentrations. Additionally, higher concentrations of flupirtine also provided protection against protein oxidation, as demonstrated by a decrease in protein carbonyls formed after treatment of rat brain homogenates with ascorbate/Fe 2+. In PC12 cell culture, flupirtine at 10–100 μM was able to attenuate H 2O 2-stimulated cell death and improve the survival by 33%.

Different direct pathways of locus coeruleus to medial prefrontal cortex and centrolateral thalamic nucleus: electrical stimulation effects on the evoked responses to nociceptive peripheral stimulation

Projections from the locus coeruleus (LC) to the centrolateral thalamus (C1) and the medial prefrontal cortex (PfCx) were studied using orthodromic and antidromic stimulation techniques. The LC is a major noradrenergic source in the central nervous system, and its descending projections provide an important source of pain suppression at spinal level. Previously, the author has described a cortico-thalamic loop involved in pain modulation. The present paper reports on a study of the participation of LC as part of an ascending pain-control system acting on the cortico-thalamic loop. Rats were anaesthetized with halothane, and single unit recordings were made in LC using glass micropipettes. Stainless steel electrodes were placed in cortex and thalamus for electrical stimulation. Stimulation in PfCx or C1 produces antidromic responses in neurons in LC. The latencies, conduction velocity and location of neurons in LC projecting to PfCx or Cl structures are described. Separate projections to both structures have significantly different conducting velocities, arriving earlier at Cl (mean conduction velocities 0.27 and standard deviation ±0.06m/s) and then at PfCx (mean conduction velocities 0.20± 0.04 m/s). The presence of orthodromic responses suggests reciprocal connections. The paper also describes the suppression of spontaneous and nociceptive-evoked activity in the PfCx and Cl following electrical stimulation in LC. It is proposed that the LC innervation could be associated with an ascending noradrenergic system acting upon a C1-PfCx pain-modulation mechanism.

Central nervous system pathways for pain transmission and pain control: Issues relevant to the practicing clinician

This review considers two areas important for the clinician: ascending pathways for pain transmission and endogenous pain control systems. The classic three-neuron pathway for pain transmission is presented and contrasted with more detailed, contemporary views on pain transmission found in the literature. The focus of the review is a discussion of spinal cord and brainstem pain control systems that modulate pain transmission. Evidence is presented which supports not only the existence of these pain modulation mechanisms but also that selected clinical procedures used by clinicians are capable of activating these mechanisms to control their patients' pain.

Chapter 7 Peripheral opioid analgesia - facts and mechanisms

This chapter focuses on the peripheral opioid analgesia that offers a variety of different facets—the mechanisms underlying them are currently only partly understood and their further elucidation is indispensible for successful introduction of these new aspects into clinical practice. Further investigations along these lines should provide new insights into the intrinsic mechanisms of pain modulation. The mechanisms involved in peripheral opioid analgesia are discussed in the chapter according to the schematic drawing that illustrates the events at the terminal region of a nociceptive nerve fibre at various developmental stages of the inflammatory process. Plane1 A represents the normal condition in the absence of inflammation or tissue injury. There is general agreement that in this case peripheral sites do not play a significant role in the antinociceptive effects of opioids. This is remarkable in view of the fact that opioid receptors (binding sites) can be demonstrated at the primary afferents of somatosensory fibres of the non-inflamed tissue. It has to be concluded that these receptors are non-functional under such conditions.

Pain management

Unrelieved post-operative pain has a number of adverse physiological effects that can impair post-operative recovery and convalescence. In patients with pre-operatively reduced organ functional reserves, such pain-induced changes may increase post-operative morbidity, and even mortality in high-risk patients. Freedom from severe pain in the immediate post-anaesthetic phase makes overall management of pain in the entire post-operative period more feasible. This will reduce unnecessary suffering, anxiety, sleep deprivation and emotional fatigue; optimal pain management may also improve cardio-respiratory functions, gastrointestinal and metabolic functions, and reduce changes in pain modulating mechanisms that cause persistent post-operative neuropathic pain. Optimal post-operative pain management is a prerequisite for early mobilization and a vigorous post-operative rehabilitation programme. The concept of ‘pre-emptive’ analgesia is still valid in that pain receiving and modulating neurones in the central nervous system will become sensitized by ongoing C-fibre nociceptive input from traumatized tissues. It is, however, not possible to prevent this sensitization by pre-treatment alone; rather it is necessary to have ongoing pain treatment as long as there is nociceptive input during the peri- and post-operative period. Anaesthesiologists have a unique opportunity to give surgical patients a flying start with post-operative pain relief by always employing analgesia-based peri- and post-anaesthetic management. A well-balanced multi-component pain relief regimen with peripheral, regional, or central neural blockade during and after surgery whenever appropriate and feasible, combined with a non-opioid and opioid analgesics should be applied. Of the non-opioid analgesics, paracetamol rectally or the prodrug propacetamol intravenously, is the safest drug in this group. It does not interfere with haemostatic mechanisms or thromboprophylactic regimens, is not ulcerogenic, and does not influence kidney function in hypovolaemic patients. The more potent NSAIDs, such as ketorolac, diclofenac, indomethacin, which also can be administered parenterally, naproxen, ketoprofen, ibuprofen, or piroxicam, all may give better pain relief than paracetamol, and they are largely safe for short-term use. However, I do worry about the potentially very serious adverse effects of some of these drugs. Glucocorticoids administered parenterally are potent analgesics and probably deserve wider use in post-operative pain management. Their adverse effects appear not to be frequent. they may have additional beneficial effects on post-operative fatigue. Whether epidural administration is more effective than parenteral administration, and whether the added risk is justifiable, remains an open question. Opioid analgesics are still the mainstay for routine post-operative pain relief. Patient-controlled opioid analgesia (PCA) is an extremely popular method with a large majority of patients who get the opportunity to use this method. However, in the immediate post-anaesthetic period, PCA is sometimes difficult to apply because of interactions with general anaesthetic drug ‘hangover’ effects such as sedation, confusion and nausea. Safe, low-dose epidural opioid administration is optimally exploited only if it is combined with a low concentration local anaesthetic. The local anaesthetic causes most of the specific beneficial effects of optimal epidural analgesia. These include improved cardiorespiratory, circulatory-haemostatic gastrointestinal, endocrine-metabolic functions. The specific spinal analgesic effect of opioid-plus-local anaesthetic can be further improved by adding an adrenergic component such as adrenaline. This low-dose epidural analgesic mixture (fentanyl-bupivacaine-adrenaline) gives excellent analgesia after major surgery, almost free of adverse effects, only if the epidural catheter is placed in a segmentally correct position: the analgesic mixture acts on opioid and adrenergic receptors and other synaptic transmission-inhibiting mechanisms of the spinal cord, not on the nerve roots. This means that the epidural catheter always will have to be above lumbar level L1–2 even for abdominoperineal or lower extremity surgery. Patient-controlled analgesia and epidural analgesia is best started in the post-anaesthesia care unit, but they can and must be implemented on surgical wards so that the patients benefit from these excellent techniques throughout the painful part of the post-operative course. This requires a major teaching and motivating programme for all nurses, surgeons and anaesthesiologists involved. Experience with implementing hospital-wide post-operative pain management programmes in two university hospitals have convinced me that this is possible only if sufficient personnel resources are available for this important task. Moreover, to ensure continuous safe post-operative pain management for most surgical patients, an ongoing programme for teaching, monitoring, quality control and quality-improvement is mandatory. This does require capital and personnel resources, but must give an overall very positive cost-benefit result for the health care system, with a more comfortable and shorter post-operative course and more satisfied patients.

Endogenous pain facilitory systems Antianalgesia and hyperalgesia

Pain inhibition has been the focus in research concerning endogenous mechanisms of pain modulation. However, recent electrophysiological, anatomical, and neurochemical studies suggest the existence of pain facilitory mechanisms as well. These should have environmental triggers, just as do pain inhibition mechanisms. There are multiple pain inhibition systems with different environmental activators, and the authors argue that a parallel situation exists with regard to pain facilitation. The authors propose two different pain facilitation mechanisms: one that is activated by environmental signals for “safety” and involves a descending pathway that opposes opiate action at the level of the spinal cord—an antianalgesia system—and another that is activated by illness and increases pain sensitivity—a hyperalgesia system. The level of pain experienced would result from the balance of activity in analgesia, antianalgesia, and hyperalgesia circuitries.