PAINAnatomy, physiology and Learning objectivespharmacology of pain After reading this article you should be able to:Ryan Moffat C draw the neural pathway(s) by which pain is perceived C outline the concepts of peripheral and central sensitization inColin P Rae chronic pain C list pharmacological agents used to modulate pain C deﬁne common pain terminology (Box 1).AbstractPain is a complex perceptual experience. The transmission of pain involvesboth peripheral and central processes and can be modulated at many levels.Peripheral sensitization causes increased afferent input to the spinal cord. body including skin, deep somatic tissue (e.g. muscles andNumerous receptors and ion channels are involved. Pain can induce physi- joints) and the viscera.ological and anatomical changes within the nervous system which are impli- C polymodal nociceptors are the most numerous type andcated in the development of neuropathic and visceral pain states. The respond to a wide range of mechanical, thermal and chemicalcomplexity of pain transmission means there are many pharmacological noxious stimuli. They are slowly conducting (<3 m/second) andtargets and multimodal therapy is required to optimize pain control. associated with prolonged ‘burning’ pain. The more rapidly conducting (5e30 m/second) Ad are associated with a brieferKeywords Allodynia; hyperalgesia; neuropathic; nociceptors; pain; ‘sharp’ pain. They are myelinated and respond to mechanicalsensitization and thermal stimuli. Approximately 15% of C-ﬁbres are ‘silent’ nociceptors; these do not respond to noxious stimuli but only become active after tissue injury or inﬂammation when theyPain is a complex experience, initiated by sensory informationconveyed from an unpleasant stimulus, greatly modiﬁed byaffective (i.e. emotional), cultural and cognitive perspectives.While the physical processes that relay a stimulus to become the‘feeling of pain’ can be described, the nature of pain as a sensa- Deﬁnitionstion and its overall signiﬁcance to the individual is unique. PainPain pathways An unpleasant sensory and emotional experience associated withThere is neither a direct nor simple ‘pain-speciﬁc’ conduit within actual or potential tissue damage, or described in terms of suchthe nervous system. Instead, the experience of pain is the ﬁnal damage.aproduct of a complex information-processing network. Following Pain is an emotion experienced in the brain; it is not like touch,delivery of a noxious stimulus, a series of electrical and chemical taste, sight, smell or hearing. Pain can be perceived as a warningevents occur. The ﬁrst stage is transduction, where external of potential damage, but can also be present when no actual harmnoxious energy is converted into electrophysiological activity. In is being done to the body.bthe second stage, transmission, this coded information is relayed Allodyniavia the spinal cord to the brainstem and thalamus. Finally, Pain due to a stimulus that does not normally provoke pain.aconnections between the thalamus and higher cortical centrescontrol perception and integrate the affective response to pain Hyperalgesia(Box 1). An increased response to a stimulus that is normally painful. The result of peripheral and central sensitizations.aTransduction The perception of a painful stimulus as more painful than normal.bWhile there is no hard-wired pain circuitry, there are physio- Dysaesthesialogically specialized peripheral sensory neurons that respond Unpleasant abnormal sensations, whether spontaneous orto noxious stimuli, namely nociceptors. These are free, unen- evoked.capsulated peripheral nerve endings found in most tissues of the Hyperpathia A painful syndrome characterized by an abnormally painful reac- tion to a stimulus, especially a repetitive stimulus, as well asRyan Moffat MBChB FRCA BsC Med Sci is a Consultant in Anaesthesia and a reduced threshold.Pain Management, New Victoria Hospital, Glasgow, UK. Conﬂicts of Sources:interest: none declared. a Internationl Association for the Study of Pain (IASP). b British Pain Society (BPS).Colin P Rae MBChB FRCA FFPMRCA is a Consultant in Anaesthesia and PainManagement, New Stobhill Hospital, Glasgow, UK. Conﬂicts of interest:none declared. Box 1ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:1 12 Ó 2010 Elsevier Ltd. All rights reserved.
PAINmay respond spontaneously or become sensitized to othersensory stimuli. Spinal and supraspinal pathways of painTransmissionThe central processes of primary afferent neurons enter the Cerebral cortex Forebrainspinal cord via the dorsal roots where they synapse with secondorder neurons in the dorsal horn. In addition descending axons Thalamusfrom the brainstem synapse in the dorsal horn and modulatenociceptive transmission. Fibres to The spinal grey matter contains the nerve cell bodies of spinal hypothalamusneurons and the white matter contains axons that ascend to or Midbraindescend from the brain. In 1952 Rexed subdivided the grey Fibres to periaqueductal Periaqueduc talmatter into 10 laminae. Laminae IeVI correspond to the dorsal grey matter grey matterhorn. C and Ad ﬁbres terminate in lamina I (marginal zone) and Fibres to Locus coeruleuslamina II (substantia gelatinosa). However, some Ad ﬁbres also reticular formatio nterminate in lamina V. Excitatory or inhibitory interneuronswhich regulate ﬂow of nociceptive information are located inlaminae V and VI. Cells which respond to innocuous stimuli such Medullaas light touch but not noxious stimuli are located in laminae III Nucleusand IV; these are known as low-threshold (LT) neurons. reticularis giganto- cellularis (NE) In addition to nociceptive and LT neurons, wide dynamicrange cells are present in lamina V. They receive input from Nucleus raph e Neospinot halami ca diverse range of neurons and have a large receptive ﬁeld. Both magn us (5-HT) tract (fast pain )innocuous and noxious stimuli are excitatory. However, in the Inhi bitory dorsal columns Palaeospinot halami csurrounding region, non-noxious stimuli (Ab ﬁbres) are inhibi- tract (slow pain )tory. This may account for the pain-relieving effects of trans- Spinal cordcutaneous electrical nerve stimulation (TENS) and the analgesia Dorsal horn (lami na I–VI ) Dorsal rootachieved by rubbing the affected area. Nociceptive input to the ganglio ndorsal horn is relayed to the higher centres in the brain via C fib resseveral ascending pathways (Figure 1). A fibres The spinothalamic tract (STT) is considered the major painpathway and originates from neurons in laminae I and VeVII.The majority of axons crosses locally and ascends con-tralaterally. Lamina I cells project to the posterior part of theventromedial nucleus of the thalamus and mediate the auto-nomic and unpleasant emotional perception of pain. Neurons in Ascendi ng nociceptive fast (red) and slow (green) pathways.the deeper laminae project to the ventral posterolateral nucleus Descendi ng inhi bitory tracts (blue).of the thalamus and carry the discriminative aspects of pain. 5-HT, 5-hydroxytryptamine; NE, norepinephrine The spinomesencephalic tract terminates primarily in theperiaqueductal gray (PAG), activating descending pain networks Figure 1which are involved in the autonomic and somatomotor aspects ofdefence reaction. Peripheral sensitization The spinoparabrachial-amygdala system originates from lamina Following tissue injury, there is a cascade of events involvingI neurons that express NK1 receptors. It is involved in the emotional primary sensory afferents, sympathetic efferents, white bloodor affective components of pain. cells and platelets that induce peripheral sensitization (Figure 2). An inﬂammatory soup, including endothelin, prostaglandin E2,Perception leukotrienes, bradykinin, cytokines, serotonin and adrenaline isAnatomical and physiological data show that several nociceptive released following tissue injury and causes increased excitability.related nuclei in the thalamus project to a number of cortical Mast cells, macrophages and neutrophils release a number of pro-areas. Recent studies using positron emission tomography (PET) inﬂammatory substances. There is an increase in the efﬁcacy ofand functional magnetic resonance imaging (fMRI) have shown transducing ion channels, a reduction in the ﬁring threshold ofchanges in blood oxygenation in those areas subserving noci- voltage-gated channels and an exaggerated response followingceptive function. Multiple cortical areas have been identiﬁed activation of these channels.including the primary and secondary somatosensory cortices, the Voltage-gated sodium channels and the capsaicin receptoranterior cinguate cortex (ACC) and the insular cortex (IC). (transient receptor potential channel V1 e TRPV1) are intimately This widely distributed cerebral activity reﬂects the complex involved in activation and sensitization of peripheral nociceptors.nature of pain involving discriminative, affective, autonomic and Cyclic adenosine monophosphate (cAMP) and protein kinasesmotor components. play an important role in the sensitizing action of many of theANAESTHESIA AND INTENSIVE CARE MEDICINE 12:1 13 Ó 2010 Elsevier Ltd. All rights reserved.
PAIN Peripheral inflammatory mediators Damage Inflammation Plasma leakage Leukotriene D4 Leukotriene B4 Bradykinin Schwann cells Macrophages Polymorph leucocytes Platelets Mast cells ATP Fibroblasts H+ Nerve growth Cytokines diHETE Prostaglandins 5-HT Histamine factor ? Nociceptive neuron Neuropeptide synthesis Substance P Prostaglandin (PGI2) Norepinephrine Sympathetic neuron 5-HT, 5-hydroxytryptamine; diHETE, dihydroxyeicosatetraenoic acid Reproduced with permission from: Wells J C D. Br Med Bull 1991; 47: 534–48.Figure 2inﬂammatory mediators. In addition, signalling cascades are C-ﬁbres in the superﬁcial dorsal horn and long outlasts theinitiated which result in acute modulation of the protein structure initiating stimulus.of ion channels, altering their function and enhancing their Secondary hyperalgesia is hyperalgesia in undamaged tissueresponsiveness. Alterations in gene expression and protein adjacent to the area of actual tissue damage. It is thought to besynthesis result in increased peptide and receptor expression due to an increased receptive ﬁeld and reduced threshold of wideresulting in more persistent alterations in sensitivity. dynamic neurons in the dorsal horn. Neurotrophic factors have an important role in the growth and The excitatory neurotransmitter glutamate has a key rolesurvival of neurons. Nerve growth factor (NGF) is increased in in the activation of both alpha-amino-3-hydroxy-5-methyl-4-iso-inﬂammatory states and induces hyperalgesia in experimental xazolepropionate (AMPA) receptors and NMDA receptors in themodels. It alters the expression of a number of mediators dorsal horn, which generate excitatory post-synaptic potentialsinvolved in peripheral sensitization. (Figure 3). Persistent excitatory transmission increases the intra- cellular calcium concentration activating second messengerCentral sensitization kinases. There is great interest in protein kinases as potential targets for new analgesic treatments.The term central sensitization is used to describe the phenomenaof wind-up, long-term potentiation and secondary hyperalgesia. Descending pain mechanisms Wind-up occurs in response to repeated noxious stimuli fromperipheral nociceptors. It refers to a process involving wide The brainstem plays a crucial role in the modulation of paindynamic range neurons in the deeper levels of the dorsal horn. It processing at the spinal cord level. Pathways originating in theis produced by repeated low-frequency activation of C-ﬁbres cortex and thalamus are relayed via the rostroventromedialcausing a progressive increase in electrophysiological response in (RVM) medulla and adjacent areas to the dorsal horn of thepost-synaptic dorsal horn neurons. The N-methyl-D-aspartate spinal cord. These areas of the brainstem also receive afferent(NMDA) receptor is closely involved in this sensitization process. input from the superﬁcial dorsal horn and from the peri- Long-term potentiation at individual synapses, thought to be aquaductal grey (PAG), nucleus tractus solitarius (NTS) andimportant in learning and memory, may also be the mechanism parabrachial nucleus, thus forming spinobulbospinal loops. Theof hyperalgesia and central sensitization. It has been shown to balance between the descending facilitatory and inhibitoryfollow high-frequency stimulation of both A-delta ﬁbres and pathways is subject to change following injury and an imbalanceANAESTHESIA AND INTENSIVE CARE MEDICINE 12:1 14 Ó 2010 Elsevier Ltd. All rights reserved.
PAIN Visceral pain Interactions between different excitatory and Visceral nociceptors are fewer, more widely distributed and not inhibitory systems in the spinal cord as well organized as somatic nociceptors. Visceral pain is often Brain and diffused and poorly localized. Visceral afferent ﬁbres respond in motorneurones a graded fashion to intensity of stimulation, rather than to Supraspinal individual stimulating modalities. They also exhibit spatial influences α2 summation, so that if a large area is stimulated, the pain 5-HT receptors threshold is lowered. This does not occur in cutaneous noci- Tissue NMDA Nitric acid ception. Referred pain is often perceived in superﬁcial body damage Wind-up Opioid structures, due to convergence of afferent information via Substance P Magnesium out Impulses segmental spinal nerves. AMPA Calcium Glutamate Substance P Pharmacology Cholecystokinin n AMPA As the transmission of pain involves many different receptors A-fibre within the peripheral and central nervous system, multimodal analgesia is best employed to optimize pain control and limit side-effects. Common drugs used in pain management include: Local γ-amino butyric non-steroidal anti-inﬂammatory drugs (NSAIDs), para- interneurones acid, cholectystokinin, cetamol and capsaicin to reduce the transduction of pain enkephalins local anaesthetics to reversibly block the transmission of pain opioids, which act at spinal and supraspinal areas to modify From Besson J. The neurobiology of pain. Lancet 1999; 353: 1610–15. afferent transmission and facilitate descending control AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; pathways 5-HT, 5-hydroxytryptamine; NMDA, N-methyl-D-aspartate. tricyclic antidepressants and selective noradrenaline reuptake inhibitors (SNRIs), which maintain monoamine levels in theFigure 3 descending pathways anticonvulsants, which act to dampen synaptic transmissionhas been implicated in the development of chronic pain states. globally, by interfering with sodium or calcium voltage-gatedSerotonin, noradrenaline and endogenous opioids are important channel function, thereby reducing excitability in sensitizedtransmitters in descending system and this is the basis for the use neurons.of antidepressants and opioids in the treatment of chronic pain. However, in addition to the physiological remedies outlined above, the personal impact of pain (i.e. on mood, anxiety, physical andNeuropathic pain social functioning) should always be considered and addressed, ifNeuropathic pain occurs as a consequence of injury or disease pain management is to be successful. Aaffecting the somatosensory system. There are many causes,including traumatic, infective, ischaemic, neoplastic and chemicallyinduced. Work in animal models suggests that the peripheral andcentral sensitization processes described already are involved in the FURTHER READINGdevelopment and maintenance of neuropathic pain. Furthermore, Castro-Lopez J, Raja S, Schmelz M. Pain 2008: An Updated Review: IASPnerve injury induces Ab afferents to sprout into the superﬁcial pain Press.transmitting areas of the dorsal horn and this process underlies the Macintyre PE, Walker SM, Rowbotham DJ. Clinical Pain Management edevelopment of allodynia and hyperalgesia. Acute Pain. 2nd edn. Arnold, 2008.ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:1 15 Ó 2010 Elsevier Ltd. All rights reserved.