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Post-operative pain
Post-operative Pain
H. Owen and M. J. Cousins
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage, and analgesia is the absence of pain on noxious stimulation (IASP definitions). Despite the prescription and administration of 'analgesics' most patients can expect unrelieved pain after surgery. 1 This most frequent therapeutic failure is blamed variously on medical staff, nursing staff or both, and on inherent properties of the techniques used (most frequently intermittent intramuscular injection of an opioid). It is now clear that patients expect pain after surgery and are reluctant to communicate pain with nursing staff (and are especially reticent with medical staff) and that this contributes significantly to the routine under-dosing. It is necessary to understand the nature of pain caused by surgery to be in a position to design appropriate therapies to control the symptoms.
reliably locate, identify and quantify a noxious stimulus, the reaction to pain needs to be modified according to the situation. However, unlike sight or hearing, pain sensation does not appear to be the result of stimulation of specific receptors designed to respond to a particular stimulus; rather it is 'an expression of dysfunction in the somatosensory system'. 2 Pain can thus be subdivided into two quite separate categories which Woolf2 has called 'physiological' pain and 'pathological' pain. These are not arbitrary distinctions. Physiological pain is the 'normal' sensation whereas 'pathological' pain is the result of an abnormal state. Since unrelieved physiological pain may give rise to pathological pain 3, prompt therapy, or better still prevention, is required.
The primary afferent nociceptor
The pathophysioiogy of pain
Examination of a peripheral nerve reveals three distinct populations of axons. These are myelinated A or (6-22p~m), A~ (2-5 ~xm) and unmyelinated C (0.3-3.0~m) fibres. The C fibres have the slowest conduction, less than 2m/s, whereas the myelinated fibres have conduction velocities ranging from 5100 m/s. Whilst there are several classes of myelinated primary afferent nerve (e.g. muscle proprioceptors) there are two groups in human cutaneous nerves: Ac~ fibres (which respond to mild mechanical stimulation) and A~ fibres (which have a mean conduction velocity of 20m/s). Thus, a brief noxious stimulus evokes two distinct sensations. The first, a result of rapid transmission of information by myelinated fibres, is a short-lasting intense sharp or tingling pain. It is followed by a separate dull, burning pain, that is poorly localised. 4
The threshold of pain detection is a property of the sensory system; it is stimulus-specific and is reproducible both in different individuals and in the same individual at different times. In contrast pain tolerance is dependent on many factors, mostly psychological, and varies greatly between individuals and in the same individual under different circumstances. These are the sensory and affective components of pain. Whilst it is important for the organism to H. Owen, MB ChB, FFARACS, FCAnaes, Senior Consultant, Senior Lecturer, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, The Flinders University of South Australia, Bedford Park, SA 5042, Australia, M. J. Cousins, MD, FFARACS, FCAnaes, Professor and Head, Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia Current Anaesthesia and Critical Care (1991)2, 25-31
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CURRENT ANAESTHESIA AND CRITICAL CARE
The A g fibres are themselves of two functionally separate groups; some respond only to noxious stimuli whereas others respond to a range of stimuli. They all have small (5 mm 2) multi-punctate receptor fields, each point being a sensitive spot about 1 mm in diameter. A g nociceptors are particularly sensitive to point stimulation and increase their discharge rate as the intensity of the stimulus increases. Up to half of Ag nociceptors also respond to heat (below the pain threshold), as well as mechanical stimulation, and so are called mechanothermal nociceptors. The others are called high-threshold mechanoreceptors, only responding, initially, to noxious stimuli. Both are capable of sensitisation, that is, following repeated noxious stimulation the threshold for activation falls and there is a progressively larger response. The majority of axons in the peripheral nerve are C fibre nociceptors. Most are polymodal nociceptors (C-PMN), that is they respond to chemical and mechanical stimuli and to heat. A C-PMN has a smaller receptive field (than the A g nociceptors) and it is a single area. Although C-PMNs are less sensitive briefly (less than 2min) after a noxious stimulus, they are sensitised by repeated high-intensity stimulation and spontaneous activity may persist after sensitisation. 5 The process of depolarisation (activation) of A g or C-PMNs by a noxious stimulus is called transduction. The resulting firing pattern of nociceptors is transmitted to the dorsal horn of the spinal cord. After injury, continued activation of nociceptors induces sensitisation. This is manifest as a decreased threshold for eliciting pain within the area of injury; this is called primary hyperalgesia where the response to a stimulus is exaggerated and prolonged and there is allodynia (pain on non-noxious stimulation of normal skin). In the surrounding uninjured tissue is a zone of secondary hyperalgesia. The primary hyperalgesia is a result of increased nociceptor responsiveness, particularly of C-PMNs to heat and mechanical stimuli. Around the zone of injury, the threshold to mechanical stimulation is unchanged so that secondary hyperalgesia appears unlikely to result from peripheral changes. Transduction and sensitisation are thought to be due to pain-producing chemicals that are released by damaged cells or synthesised from substrates released by the damage. Histamine and potassium both excite C-PMNs and acetylcholine, ATP, 5HT, low pH, prostaglandins, leukotrienes, and bradykinin can contribute to pain and hyperalgesia. Bradykinin is thought to be one of the more important mediators of C-PMN excitation. It acts through at least two second messengers, inositol triphosphate (IP3) and diacyglycerol (DAG) which is known to act on a protein kinase to generate an excitatory inward current. The prostaglandins enhance excitability by a complementary mechanism. A series of peptide antagonists of bradykinin have recently been discovered which may have a role in pain therapy. 6 Capsaicin acts
selectively on C-PMNs, opening a cation selective channel; there is no second messenger involved, and the channel is directly gated by the ligand. 6 Nociceptors themselves can release sensitising substances (e.g. substance P). Postganglionic sympathetic efferents are also involved in sensitisation (possibly through release of ATP or a neuropeptide) and leukocytes can also contribute. Substance P, released by nociceptors, produces vasodilation and oedema and also causes histamine release from mast cells and ser-otonin release from platelets, which causes further inflammatory changes. In response to tissue injury, antidromic activation of C-fibre afferents also occurs as the 'Triple Response' (heat, redness and swelling), described originally by Lewis. These events produce enhanced sensation and also prolong pain beyond the boundary of the stimulus. The primary afferent nociceptor not only signals tissue damage but also acts to initiate tissue repair by increased blood flow and oedema. However, the induced changes in peripheral sensitivity are insufficient to explain secondary hyperalgesia completely; substantial evidence supports additional central mechanisms of secondary hyperalgesia. 3
The dorsal horn The cell bodies of all peripheral afferents are located in the dorsal root ganglion (DRG). Most axons project from the DRG to the spinal cord through the dorsal root although some are contained also in the ventral root and there is much branching of axons near the ganglion. As the dorsal root approaches the spinal cord the A~ and C fibres become concentrated in the ventrolateral part of the root. By the time the root reaches the surface of the cord the C fibres are quite separate from the Ag fibres, and all fibres bifurcate into ascending and descending branches to form Lissauer's tract. After a variable distance the branches enter the spinal grey matter and project densely to laminae I and II of the dorsal horn, giving rise to extremely complex terminal fields. The distribution of the terminal branches is somatotopographically ordered so that their mediolateral and rostrocaudal position in the dorsal horn is related to their peripheral receptive fields and the dorsolateral distribution reflects their modality responsiveness and threshold, z Lamina I (also called the marginal layer as it lies as a cap over the dorsal margin of the spinal grey) contains mostly nociceptive specific or 'high threshold' neurones that receive inputs from both A g and C fibres. A few neurones are present which also respond to inputs from nociceptors and from nonnociceptive mechanoreceptors - these are the 'wide dynamic range' (WDR) neurones. The majority of lamina I cells project to the thalamus (and to further sites) although there are a significant number of local
POST-OPERATIVE PAIN
connections. In contrast the majority of lamina II cells are interneurones that make mostly local connections within lamina II (substantia gelatinosa). There are however many cells in laminae I, III, IV and V that receive inputs from cells in the substantia gelatinosa. Thus lamina I cells receive direct and indirect nociceptive inputs. Laminae III and IV cells respond mainly to non-noxious stimuli. Lamina V is another layer which, like lamina I, responds maximally to noxious stimuli. However, there is greater convergence (so that receptive fields are larger in lamina V than lamina I) and more cells are of the WDR type. Lamina V receives some direct inputs from nociceptors but many are from interneutones from laminae I and II. This may explain some of the convergence. Many lamina V cells project to the thalamus and brain stem. Proprioceptive information from the limbs is received by lamina VI which exists only in the cervical and lumbar enlargements. Cells in lamina VII and VIII are also responsible for transmission of nociceptive information to the thalamus and brain stem. However, they show the greatest convergence of their receptive fields, which can even be bilateral and also include visceral receptors. Finally, the central canal lamina (lamina X) has small, predominantly nociceptive, receptive fields which project centrally on both sides. The receptive field properties of dorsal horn neurones are, however, not 'hard-wired'; variation can occur as a result of descending influences, some drugs and nociceptive afferent input. The size of the receptive field increases after peripheral injury or cond!tioning stimuli and many even recruit contralateral inputsT; these cells may then respond to a wider range of stimuli. It is the C fibre afferent input which produces this central sensitisation, the mechanism of which has been explained by Woolf. 2 Three different actions of C fibres on the dorsal horn are proposed: 1. Transfer of information on location, onset duration and intensity of noxious stimuli is produced by direct monosynaptic contact. The fast neurotransmitter is an excitatory amino acid (EAA) such as glutamate and the receptors proposed are the n-methyl-D-aspartate (NMDA), quisqualate kainate or similar. 8 2. Neuromodulators are co-released by the same terminal as the fast transmitters. Summation of the resulting slow excitatory potentials with repeated stimulation is called 'wind-up', i.e. an identical stimulus can induce successively larger responses.2 The peptides substance P and neurokinin-A are released from the same afferent terminals as glutamate and produce slow potentials which last for tens of seconds and this is important in temporal summation. Thus the subliminal zone of the receptor field of a dorsal horn neurone can be recruited and inputs that were once subthreshold can now trigger a response. Somatostatin and
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calcitonin gene-related peptide may also be involved in nociceptive neurotransmission. 3. Long lasting effects are also produced by brief C fibre inputs. In addition to the slow potentials, alterations in cell excitability are triggered both through second messengers and the NMDA and quisqualate receptors. The second messengers include Ca 2+, cAMP, cGMP and IP3 and can, by acting on protein kinases, membrane bound receptors, etc., influence cell behaviour such as long term potentiation (LTP) of response. Ca 2÷ allowed to pass through NMDA receptors may induce gene expression. 8 The c-los protooncogene has received much attention recently as a marker of nociception in animals. Oncogenes are segments of DNA that, when expressed, mimic or exaggerate a step in the chain of events induced by the action of a growth factor or hormone in normal cells. If close identity exists between the DNA sequences of a normal gene and a viral oncogene it is called a cellular oncogene (c-one) o r proto-oncogene. After a painful stimulus c-fos is expressed within 10min and the protein produced, Fos, binds with the protein Jun (from the c-jun proto-oncogene). This dimer binds to a nuclear regulatory site, AP-1, which controls transcription of adjacent genes that encode cellular products including neuropeptides. 9 In this way expression of prodynorphins, proenkephalins and nerve growth factor occurs which may affect pain sensation and synaptic remodelling. Both trauma and induced inflammation result in c-los expression; opioid analgesics administered before the event markedly reduce its expression. 1° The net results of events 1-3 are that continued C fibre afferent input results in amplification of response, afterdischarge and spatial spread.
Sympathetic nerves and nociception Nociceptive input from the body to the dorsal horn region results in reflex increases in sympathetic activity in cells of the intermediolateral cell column of the spinal cord and in turn in sympathetic ganglia. Sympathetic efferent activity is thus increased and this may contribute to nociception by peripheral release of noradrenaline (NA) and other transmitters, which sensitise nociceptors to allergic substances such as bradykinin and K + (see above). Thus a 'vicious circle' may develop. Sensitisation of nociceptors by NA was formerly believed to occur only in areas of damaged tissue. However there is recent evidence to suggest that prolonged contraction in muscle may change the neurochemical milieu so that sensitisation by NA can occur without overt tissue damage. Another mechanism that has been invoked for sympathetic efferents and nociception is via ephaptic connections, where sympathetic fibres form
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abnormal links with nociceptive afferents, permitting either electrical or neurochemical activation. Persisting abnormal levels of sympathetic activity, by either mechanism above, may lead to a syndrome referred to by many names including causalgia (usually reserved for pain associated with damage to major nerves), reflex sympathetic dystrophy (minor or no nerve damage), shoulder-hand syndrome, Sudeck's atrophy, etc. Recently it has been suggested that involvement of sympathetic nervous system should be confirmed by relief of pain by sympathetic nerve blocks, and that only such cases should be referred to as 'sympathetically maintained pain' (SMP).
Musculoskeletal and visceral pain Cutaneous pain sensation is necessary for self-preservation and accurate localisation of the noxious stimuli is advantageous. Such precision is not required for the deep tissues. Musculoskeletal pain is also a result of A ~ and C fibre activation. Joints are innervated by primary afferents which respond only to extremes of movement or pressure (about half the A ~ and most of the C fibres), the remainder responding to less intense stimulation. With inflammation, all the afferent nociceptors become responsive to small movements and more sensitive to pressure. Muscle is also innervated by myelinated an unmyelinated primary afferents but many of the C fibres respond to a wide range of stimuli (heat, pressure and chemicals) so that they behave like cutaneous C-PMNs. There is an additional population of unmyelinated afferents that discharge maximally in response to muscle contraction in an ischaemic environment. Even less is known of visceral nociceptive afferents. The viscera appear insensitive to heat, cutting or pinching, although there are nociceptive responses to stretching. Thus, surgical technique does play a part in the genesis of pain. Visceral nociceptor stimulation results in autonomic changes (e.g. increases or decreases in blood pressure) as well as complaints of pain. Visceral pain is of slow onset and most frequently described as dull or aching. It is poorly localised and may be felt to originate from a site remote from the stimulus (referred pain). Whilst the deep-seated pain is of vague origin, pain referred to the body surface has a clear-cut boundary and can be mapped objectively, using the accompanying cutaneous hypersensitivity. These areas, called Head's zones, n have margins associated with the cutaneous innervation of the same spinal segments that innervate the diseased viscus. Referred pain from the diaphragm is complicated by its dual innervation. The central part of the diaphragm is innervated by the phrenic nerve; irritation causes a sharp pain in the shoulder and a hyperalgesic area approximating to the C3 and Ca dermatomes. When the outer region is stimulated, pain is felt in the lower chest and upper abdominal wall which are
innervated jointly with the diaphragm by intercostals. This holds true for both surfaces of the diaphragm. All viscera are innervated by two routes, either via afferents that follow a similar route to the spinal cord as afferents from somatic structures, or with autonomic efferents. Detailed study of the splanchnic nerves reveals that afferent fibres synapse with dorsal horn cells in laminae I and V. Most dorsal horn cells receiving visceral input also receive a somatic input. Visceral nociceptive afferent fibres are best described as such (rather than 'sympathetic afferents'). Sympathetic efferents may play an indirect role in nociception as described in the section above. Several mechanisms have been proposed for referred pain including branched primary afferents, reflex activation of nociceptors and perceptual projection. All may occur, but the most widely held view is that the mislocalisation results from sparse innervation of viscera and the convergence of afferent information from viscera and from superficial segmentally related tissue on to the same dorsal horn projection neurones. Referred pain is important in diagnosing the underlying disorder and should be distinguished from non-referred pain as one step in deciding appropriate pain therapies.
Central projection of nociceptive information Nociceptive information is transmitted to the brain stem and thalamus in the anterolateral (spinothalamic) tracts of the spinal cord on the opposite side to the stimulus. Some information, though inadequate to localise the source of a noxious stimulus, passes up ipsilateral tracts so that disruption of the anterolateral tracts (e.g. by cordotomy) is followed by a variable partial recovery of sensation. The ipsilateral tracts terminate in 'the intralaminar thalamus; the crossed tract axons separate into lateral and medial divisions, which terminate in the ventrobasal (lateral) nucleus and the posterior nuclear group, and the central lateral (medial) nucleus of the interlaminar complex and the nucleus submedius respectively. The lateral thalamic nuclei receive input from cells arising in lamina f (nociceptive specific) and V (WDR) with small receptive fields and project directly to the somatosensory cortex in a topographical arrangement. The medial nuclei receive their input from spinal cells located in deeper laminae VI, VII or VIII which have large receptive fields and project widely to the ipsilateral cortex and the frontal lobe. The brainstem reticular formation receives input from laminae V, VI, VII and VIII via the spinoreticular tract and makes bilateral contributions to the medial thalamic nuclei. The medial nuclei have connections with the frontal lobes. The frontal lobe is not concerned with the sensory-discriminative aspects of noxious stimuli (that is the role of the somatosensory cortex) but with the affective-motivational components of pain. 5
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Descending inhibition Electrical stimulation of several areas of the midbrain including the peri-aqueductal grey matter (PAG) and rostroventral medulla (RVM) inhibit dorsal horn noeiceptive neurones. The RVM receives input from the lateral and dorsolateral pontine tegmentum. Neurones in the RVM and pons project directly to the spinal cord and connect with neurones in laminae I, II and V in the dorsal horn through the dorsolateral funiculus. Many cells that originate in the pons contain noradrenaline whereas many cells projecting from the RVM are serotinergic, particularly the Nucleus Raphe Magnus (NRM). There are enkephalinergic inhibitory interneurones in the substantia gelatinosa. These are excited by the serotinergic cells and then inhibit nociception. Exogenous opioids mimic this effect on the dorsal horn neurones. Enkephalinergic cells are found also in the PAG and RVM, and opioids also act on these centres to modulate pain sensation. This is an extremely simple description. There are many other connections and many other amines and peptides released by neurones in the brain and spinal cord. Whilst the full story has yet to be elucidated, the information available at present can be used to develop better pain therapies.
Post-operative pain therapies It is clear from the above that the conduct of anaesthesia may affect subsequent pain sensation profoundly. The nociceptive barrage called surgery must be modified to prevent changes occurring in the dorsal horn. 2 It has been reported that small doses of opioid administered before noxious stimulation can suppress hyperexcitability, whereas larger doses of opioid are required to achieve the same response once hyperexcitability has become established. 12'13 Post-operative pain is not simply the sustained activation of pain pathways; it is the result of changes in the system, from transduction to perception. It is only recently that clinical implications for pain management of this 'plasticity' of the nervous system have been realised. 13 Studies have demonstrated that a decrease in requirement for post-operative analgesic medication follows the use of opioid pre-medication, local anaesthetic peripheral nerve blockade (prior to surgery), epidural or spinal anaesthesia and non-steroidal anti-inflammatory drugs (prior to surgery). In 1911 anaesthetists were told that 'inhalational anaesthesia puts asleep only a portion of the brain and is at best only a veneer' and that combining neural blockade with general anaesthesia protects the nervous system. ~4 Three quarters of a century later the neurophysiological basis for such comments has been described. 2 Post-operatively, meas.ures should be directed towards pain prophylaxis and the prevention of
pathological changes in the central nervous system. These can be: 1. Interruption of the flow of sensation, e.g. at a neuronal level by continuous epidural or spinal analgesia with local anaesthetic, or at a synaptic level by block of the neurotransmitters of the primary afferent nociceptor. 2. Prevention of hyperalgesia both peripherally, e.g. with non-steroidal anti-inflammatory drugs (NSAIDs), and centrally, e.g. by low-dose opioid therapy. 3. Activation of pain-modulating pathways, e.g. by psychological measures, or with stimulation-produced analgesia, e.g. transcutaneous electrical nerve stimulation. 4. Augmentation of pain-modulating pathways, e.g. by administration of exogenous substances acting on opioid, noradrenergic or serotinergic receptors. 5. Combination therapies which include elements of the above categories.
1. Interruption of sensation Total blockade of pain sensation after abdominal surgery is possible by continuous epidural blockade. However, central changes still occur and studies have revealed that the neuroendocrine response to surgery is not modified significantly by this technique. In addition this therapy requires special monitoring and nursing. It has been reported that continuous epidural analgesia reduces mortality in patients warranting admission to ICU post-operatively. 15 A conclusion of the most recent symposium on the influences of currently used anaesthetic procedures on surgical sequelae was that the effects of anaesthesia and analgesia on outcome are controversial. 16 If synaptic transmission between nociceptive afferents and dorsal horn neurones can be blocked, analgesia results. Fast transmission by excitatory amino acids is blocked by ~-opioid receptor agonists. The effects of such agents at different receptor subtypes (e.g. NMDA and quisqualate) suggest that new types of analgesic drugs can be developed. 6
2. Prevention of hyperalgesia Peripheral sensation can be reduced by good pain control, which defuses the effect of feed-forward sympathetic efferents. NSAIDs and steroids also reduce nociception at this level, as do bradykinin antagonists. 6 Wind-up has been discussed above. The interaction with prior depolarisation at the dorsal horn leading to this process can be abolished by small 'preventive' doses of opioids. Other NMDA antagonists, e.g. ketamine, can prevent wind-up. Prompt control of pain leading to lower dose requirements (e.g. with patient-controlled analgesia; PCA) can be explained by control of wind-up.
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3. Activation of pain-modulating pathways
Table - - Examples of different scales for pain measurement
Activation of descending inhibitory pathways is important in the response to placebo analgesics, which can be naloxone-reversible. Cognitive pain control techniques also act by this mechanism and so too rhay transcutaneous nerve stimulation and acupuncture.
0= 1= 2= 3= 4=
no pain Mild pain Moderate pain Severe pain Unbearable pain*
0 1 2 3 4
= = = = =
no pain Sometimes moderate pain Always moderate pain Sometimes severe pain Always moderate, sometimes severe pain. 5 = Discontinuation of therapy due to inefficacy
* This category frequently omitted
4. Augmentation of pain-modulating pathways Augmentation of the inhibitory pathways is extremely important and a major component of opioid analgesia occurs through this mechanism. Surgeons often express the fear that analgesia will mask signs of developing complications (e.g. biliary leak after cholecystectomy). It should be emphasised that opioids can prevent central sensitisation (pathological pain) and augment descending controls but they do not block physiological (incident) pain very effectively. For example, opioids administered for analgesia in patients with an acute abdomen alter physical signs in proportion to dosage, but have no effect on clinical diagnosis. 17
5. Combination therapy The major advances in post-operative pain treatment have involved combination therapies or 'balanced analgesia'. A combination of NSAID and opioid is very effective after surgery and combinations of epidural local anaesthetic and opioid are also effective. Recently, epidural local anaesthetics plus opioid have been combined with NSAID, resulting in complete pain relief at rest and very little pain on movement, as
Prevention of persistent post-surgical pain Not all post-operative pain resolves. Surgery may initiate on-going pain syndromes which can arise as a result of the interplay of nociception, neuropathy and environmental/psychological factors. Identified predisposing or risk factors include a genetic influence in neuroma formation, duration and severity of pain both before and after surgery, surgical technique and age. 3 Some data suggest that effective pain control is instrumental in preventing the development of persistent post-surgical pain syndromes.
Measurement of post-operative pain The monitoring of post-operative pain is also undergoing significant change. The rating scales used range from the bipolar pain/no pain responses through variations of ordered categorical scales (Table) to the 10cm visual analogue scale with 100 pain divisions. Pain rating scales may be applied at a particular time or are applied retrospectively. Excessively frequent
measurement of post-operative pain can, however, be counterproductive. There is now a trend away from simply examining pain or pain relief towards restoration of function along with analgesia. Thus more studies are being undertaken that consider pain both at rest and on movement, on objective measurement of the physiological response to pain therapies (e.g. nitrogen balance or respiratory function) and on rehabilitation measures (e.g. time to sit, stand or be discharged home). 15'16'18 Measures of outcome, in addition to audit of structure and process, will become increasingly important. The range of pain-controlling therapies currently used clinically has been reviewed recently by Mitchell and Smith. 2° The recent developments outlined above now need to be applied.
Conclusions An understanding of the neurobiology and pathophysiology of acute pain allows us to analyse the shortcomings of our present pain therapies. The information to improve our use of the drugs available at present exists but has yet to be widely implemented. New analgesics are being developed but it is likely that they too will be most effective when used in combination therapies.
References 1. Owen H, McMillan V, Rogowski D. Post-operative pain therapy: a survey of patients' expectations and their experiences. Pain 1990; 41:303-308 2. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63:139-146 3. Cousins MJ. Acute pain and the injury response: immediate and prolonged effects. Reg Anesth 1989; 14:162-179 4. Yaksh TL. Neurologic mechanisms of pain. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade (2nd ed) Philadelphia: JB Lippincott, 1988:791-844 5. Fields HL. Pain. New York: McGraw Hill, 1987 6. Rang HP. The nociceptive afferent neurone as a target for new types of analgesic drug. Pain 1990; Suppl 5:$249 7. Woolf CJ. Evidence for a central component of post injury pain hypersensitivity. Nature 1983; 308:686-688 8. Wilcox GL. Transmission and modulation of pain at the spinal level. Pain 1990; suppl 5:$247-8 9. Sonnenberg JL, Ranscher FR III, Morgan JI, Curran T. Regulation of proenkephalin by Fos and Jun. Science 1989; 246:1622-1625 10. Presley RW, Menetrey D, Levine JD, Basbaum AI. Systemic morphine suppresses noxious stimulus-evoked Fos proteinlike immunoreactivity in the rat spinal cord. J Neurosci 1990; 10:323-335
POST-OPERATIVE PAIN 11. Head H. On disturbances of sensation with especial reference to the pain of visceral disease. Brain 1893; 16:1-132 12. Wall PD. The prevention of post-operative pain. Pain 1988; 33:289-290 13. McQuay HJ, Dickenson AH. Implications of nervous system plasticity for pain management. Anaesthesia 1990; 45: 101102 14. Crile GW. Nitrous oxide anaesthesia and a note on anociassociation, a new principle in operative surgery. Surg Gynecol Obstet 1911; 13:170-173 15. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high risk surgical patients. Anesthesiology 1987; 66:729-736
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16. Covino BG. Influence of anaesthetic procedures on surgical sequelae. Acta Chir Scand 1989; 550 17. Zoltie N, Cust MP. Analgesia in the acute abdomen. Ann R Coll Surg 1986; 68:209-210 18. Kehlet H. Surgical stress: The role of pain and analgesia. Br J Anaesth 1989; 63:189-195 19. Chapman CR, Casey KL, Dubner R, Floey KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985; 22:1-31 20. Mitchell RWD, Smith G. The control of acute post-operative pain. Br J Anaesth 1989; 63:147-158
H. Owen and M. J. Cousins
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage, and analgesia is the absence of pain on noxious stimulation (IASP definitions). Despite the prescription and administration of 'analgesics' most patients can expect unrelieved pain after surgery. 1 This most frequent therapeutic failure is blamed variously on medical staff, nursing staff or both, and on inherent properties of the techniques used (most frequently intermittent intramuscular injection of an opioid). It is now clear that patients expect pain after surgery and are reluctant to communicate pain with nursing staff (and are especially reticent with medical staff) and that this contributes significantly to the routine under-dosing. It is necessary to understand the nature of pain caused by surgery to be in a position to design appropriate therapies to control the symptoms.
reliably locate, identify and quantify a noxious stimulus, the reaction to pain needs to be modified according to the situation. However, unlike sight or hearing, pain sensation does not appear to be the result of stimulation of specific receptors designed to respond to a particular stimulus; rather it is 'an expression of dysfunction in the somatosensory system'. 2 Pain can thus be subdivided into two quite separate categories which Woolf2 has called 'physiological' pain and 'pathological' pain. These are not arbitrary distinctions. Physiological pain is the 'normal' sensation whereas 'pathological' pain is the result of an abnormal state. Since unrelieved physiological pain may give rise to pathological pain 3, prompt therapy, or better still prevention, is required.
The primary afferent nociceptor
The pathophysioiogy of pain
Examination of a peripheral nerve reveals three distinct populations of axons. These are myelinated A or (6-22p~m), A~ (2-5 ~xm) and unmyelinated C (0.3-3.0~m) fibres. The C fibres have the slowest conduction, less than 2m/s, whereas the myelinated fibres have conduction velocities ranging from 5100 m/s. Whilst there are several classes of myelinated primary afferent nerve (e.g. muscle proprioceptors) there are two groups in human cutaneous nerves: Ac~ fibres (which respond to mild mechanical stimulation) and A~ fibres (which have a mean conduction velocity of 20m/s). Thus, a brief noxious stimulus evokes two distinct sensations. The first, a result of rapid transmission of information by myelinated fibres, is a short-lasting intense sharp or tingling pain. It is followed by a separate dull, burning pain, that is poorly localised. 4
The threshold of pain detection is a property of the sensory system; it is stimulus-specific and is reproducible both in different individuals and in the same individual at different times. In contrast pain tolerance is dependent on many factors, mostly psychological, and varies greatly between individuals and in the same individual under different circumstances. These are the sensory and affective components of pain. Whilst it is important for the organism to H. Owen, MB ChB, FFARACS, FCAnaes, Senior Consultant, Senior Lecturer, Department of Anaesthesia and Intensive Care, Flinders Medical Centre, The Flinders University of South Australia, Bedford Park, SA 5042, Australia, M. J. Cousins, MD, FFARACS, FCAnaes, Professor and Head, Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia Current Anaesthesia and Critical Care (1991)2, 25-31
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The A g fibres are themselves of two functionally separate groups; some respond only to noxious stimuli whereas others respond to a range of stimuli. They all have small (5 mm 2) multi-punctate receptor fields, each point being a sensitive spot about 1 mm in diameter. A g nociceptors are particularly sensitive to point stimulation and increase their discharge rate as the intensity of the stimulus increases. Up to half of Ag nociceptors also respond to heat (below the pain threshold), as well as mechanical stimulation, and so are called mechanothermal nociceptors. The others are called high-threshold mechanoreceptors, only responding, initially, to noxious stimuli. Both are capable of sensitisation, that is, following repeated noxious stimulation the threshold for activation falls and there is a progressively larger response. The majority of axons in the peripheral nerve are C fibre nociceptors. Most are polymodal nociceptors (C-PMN), that is they respond to chemical and mechanical stimuli and to heat. A C-PMN has a smaller receptive field (than the A g nociceptors) and it is a single area. Although C-PMNs are less sensitive briefly (less than 2min) after a noxious stimulus, they are sensitised by repeated high-intensity stimulation and spontaneous activity may persist after sensitisation. 5 The process of depolarisation (activation) of A g or C-PMNs by a noxious stimulus is called transduction. The resulting firing pattern of nociceptors is transmitted to the dorsal horn of the spinal cord. After injury, continued activation of nociceptors induces sensitisation. This is manifest as a decreased threshold for eliciting pain within the area of injury; this is called primary hyperalgesia where the response to a stimulus is exaggerated and prolonged and there is allodynia (pain on non-noxious stimulation of normal skin). In the surrounding uninjured tissue is a zone of secondary hyperalgesia. The primary hyperalgesia is a result of increased nociceptor responsiveness, particularly of C-PMNs to heat and mechanical stimuli. Around the zone of injury, the threshold to mechanical stimulation is unchanged so that secondary hyperalgesia appears unlikely to result from peripheral changes. Transduction and sensitisation are thought to be due to pain-producing chemicals that are released by damaged cells or synthesised from substrates released by the damage. Histamine and potassium both excite C-PMNs and acetylcholine, ATP, 5HT, low pH, prostaglandins, leukotrienes, and bradykinin can contribute to pain and hyperalgesia. Bradykinin is thought to be one of the more important mediators of C-PMN excitation. It acts through at least two second messengers, inositol triphosphate (IP3) and diacyglycerol (DAG) which is known to act on a protein kinase to generate an excitatory inward current. The prostaglandins enhance excitability by a complementary mechanism. A series of peptide antagonists of bradykinin have recently been discovered which may have a role in pain therapy. 6 Capsaicin acts
selectively on C-PMNs, opening a cation selective channel; there is no second messenger involved, and the channel is directly gated by the ligand. 6 Nociceptors themselves can release sensitising substances (e.g. substance P). Postganglionic sympathetic efferents are also involved in sensitisation (possibly through release of ATP or a neuropeptide) and leukocytes can also contribute. Substance P, released by nociceptors, produces vasodilation and oedema and also causes histamine release from mast cells and ser-otonin release from platelets, which causes further inflammatory changes. In response to tissue injury, antidromic activation of C-fibre afferents also occurs as the 'Triple Response' (heat, redness and swelling), described originally by Lewis. These events produce enhanced sensation and also prolong pain beyond the boundary of the stimulus. The primary afferent nociceptor not only signals tissue damage but also acts to initiate tissue repair by increased blood flow and oedema. However, the induced changes in peripheral sensitivity are insufficient to explain secondary hyperalgesia completely; substantial evidence supports additional central mechanisms of secondary hyperalgesia. 3
The dorsal horn The cell bodies of all peripheral afferents are located in the dorsal root ganglion (DRG). Most axons project from the DRG to the spinal cord through the dorsal root although some are contained also in the ventral root and there is much branching of axons near the ganglion. As the dorsal root approaches the spinal cord the A~ and C fibres become concentrated in the ventrolateral part of the root. By the time the root reaches the surface of the cord the C fibres are quite separate from the Ag fibres, and all fibres bifurcate into ascending and descending branches to form Lissauer's tract. After a variable distance the branches enter the spinal grey matter and project densely to laminae I and II of the dorsal horn, giving rise to extremely complex terminal fields. The distribution of the terminal branches is somatotopographically ordered so that their mediolateral and rostrocaudal position in the dorsal horn is related to their peripheral receptive fields and the dorsolateral distribution reflects their modality responsiveness and threshold, z Lamina I (also called the marginal layer as it lies as a cap over the dorsal margin of the spinal grey) contains mostly nociceptive specific or 'high threshold' neurones that receive inputs from both A g and C fibres. A few neurones are present which also respond to inputs from nociceptors and from nonnociceptive mechanoreceptors - these are the 'wide dynamic range' (WDR) neurones. The majority of lamina I cells project to the thalamus (and to further sites) although there are a significant number of local
POST-OPERATIVE PAIN
connections. In contrast the majority of lamina II cells are interneurones that make mostly local connections within lamina II (substantia gelatinosa). There are however many cells in laminae I, III, IV and V that receive inputs from cells in the substantia gelatinosa. Thus lamina I cells receive direct and indirect nociceptive inputs. Laminae III and IV cells respond mainly to non-noxious stimuli. Lamina V is another layer which, like lamina I, responds maximally to noxious stimuli. However, there is greater convergence (so that receptive fields are larger in lamina V than lamina I) and more cells are of the WDR type. Lamina V receives some direct inputs from nociceptors but many are from interneutones from laminae I and II. This may explain some of the convergence. Many lamina V cells project to the thalamus and brain stem. Proprioceptive information from the limbs is received by lamina VI which exists only in the cervical and lumbar enlargements. Cells in lamina VII and VIII are also responsible for transmission of nociceptive information to the thalamus and brain stem. However, they show the greatest convergence of their receptive fields, which can even be bilateral and also include visceral receptors. Finally, the central canal lamina (lamina X) has small, predominantly nociceptive, receptive fields which project centrally on both sides. The receptive field properties of dorsal horn neurones are, however, not 'hard-wired'; variation can occur as a result of descending influences, some drugs and nociceptive afferent input. The size of the receptive field increases after peripheral injury or cond!tioning stimuli and many even recruit contralateral inputsT; these cells may then respond to a wider range of stimuli. It is the C fibre afferent input which produces this central sensitisation, the mechanism of which has been explained by Woolf. 2 Three different actions of C fibres on the dorsal horn are proposed: 1. Transfer of information on location, onset duration and intensity of noxious stimuli is produced by direct monosynaptic contact. The fast neurotransmitter is an excitatory amino acid (EAA) such as glutamate and the receptors proposed are the n-methyl-D-aspartate (NMDA), quisqualate kainate or similar. 8 2. Neuromodulators are co-released by the same terminal as the fast transmitters. Summation of the resulting slow excitatory potentials with repeated stimulation is called 'wind-up', i.e. an identical stimulus can induce successively larger responses.2 The peptides substance P and neurokinin-A are released from the same afferent terminals as glutamate and produce slow potentials which last for tens of seconds and this is important in temporal summation. Thus the subliminal zone of the receptor field of a dorsal horn neurone can be recruited and inputs that were once subthreshold can now trigger a response. Somatostatin and
27
calcitonin gene-related peptide may also be involved in nociceptive neurotransmission. 3. Long lasting effects are also produced by brief C fibre inputs. In addition to the slow potentials, alterations in cell excitability are triggered both through second messengers and the NMDA and quisqualate receptors. The second messengers include Ca 2+, cAMP, cGMP and IP3 and can, by acting on protein kinases, membrane bound receptors, etc., influence cell behaviour such as long term potentiation (LTP) of response. Ca 2÷ allowed to pass through NMDA receptors may induce gene expression. 8 The c-los protooncogene has received much attention recently as a marker of nociception in animals. Oncogenes are segments of DNA that, when expressed, mimic or exaggerate a step in the chain of events induced by the action of a growth factor or hormone in normal cells. If close identity exists between the DNA sequences of a normal gene and a viral oncogene it is called a cellular oncogene (c-one) o r proto-oncogene. After a painful stimulus c-fos is expressed within 10min and the protein produced, Fos, binds with the protein Jun (from the c-jun proto-oncogene). This dimer binds to a nuclear regulatory site, AP-1, which controls transcription of adjacent genes that encode cellular products including neuropeptides. 9 In this way expression of prodynorphins, proenkephalins and nerve growth factor occurs which may affect pain sensation and synaptic remodelling. Both trauma and induced inflammation result in c-los expression; opioid analgesics administered before the event markedly reduce its expression. 1° The net results of events 1-3 are that continued C fibre afferent input results in amplification of response, afterdischarge and spatial spread.
Sympathetic nerves and nociception Nociceptive input from the body to the dorsal horn region results in reflex increases in sympathetic activity in cells of the intermediolateral cell column of the spinal cord and in turn in sympathetic ganglia. Sympathetic efferent activity is thus increased and this may contribute to nociception by peripheral release of noradrenaline (NA) and other transmitters, which sensitise nociceptors to allergic substances such as bradykinin and K + (see above). Thus a 'vicious circle' may develop. Sensitisation of nociceptors by NA was formerly believed to occur only in areas of damaged tissue. However there is recent evidence to suggest that prolonged contraction in muscle may change the neurochemical milieu so that sensitisation by NA can occur without overt tissue damage. Another mechanism that has been invoked for sympathetic efferents and nociception is via ephaptic connections, where sympathetic fibres form
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C U R R E N T A N A E S T H E S I A A N D CRITICAL C A R E
abnormal links with nociceptive afferents, permitting either electrical or neurochemical activation. Persisting abnormal levels of sympathetic activity, by either mechanism above, may lead to a syndrome referred to by many names including causalgia (usually reserved for pain associated with damage to major nerves), reflex sympathetic dystrophy (minor or no nerve damage), shoulder-hand syndrome, Sudeck's atrophy, etc. Recently it has been suggested that involvement of sympathetic nervous system should be confirmed by relief of pain by sympathetic nerve blocks, and that only such cases should be referred to as 'sympathetically maintained pain' (SMP).
Musculoskeletal and visceral pain Cutaneous pain sensation is necessary for self-preservation and accurate localisation of the noxious stimuli is advantageous. Such precision is not required for the deep tissues. Musculoskeletal pain is also a result of A ~ and C fibre activation. Joints are innervated by primary afferents which respond only to extremes of movement or pressure (about half the A ~ and most of the C fibres), the remainder responding to less intense stimulation. With inflammation, all the afferent nociceptors become responsive to small movements and more sensitive to pressure. Muscle is also innervated by myelinated an unmyelinated primary afferents but many of the C fibres respond to a wide range of stimuli (heat, pressure and chemicals) so that they behave like cutaneous C-PMNs. There is an additional population of unmyelinated afferents that discharge maximally in response to muscle contraction in an ischaemic environment. Even less is known of visceral nociceptive afferents. The viscera appear insensitive to heat, cutting or pinching, although there are nociceptive responses to stretching. Thus, surgical technique does play a part in the genesis of pain. Visceral nociceptor stimulation results in autonomic changes (e.g. increases or decreases in blood pressure) as well as complaints of pain. Visceral pain is of slow onset and most frequently described as dull or aching. It is poorly localised and may be felt to originate from a site remote from the stimulus (referred pain). Whilst the deep-seated pain is of vague origin, pain referred to the body surface has a clear-cut boundary and can be mapped objectively, using the accompanying cutaneous hypersensitivity. These areas, called Head's zones, n have margins associated with the cutaneous innervation of the same spinal segments that innervate the diseased viscus. Referred pain from the diaphragm is complicated by its dual innervation. The central part of the diaphragm is innervated by the phrenic nerve; irritation causes a sharp pain in the shoulder and a hyperalgesic area approximating to the C3 and Ca dermatomes. When the outer region is stimulated, pain is felt in the lower chest and upper abdominal wall which are
innervated jointly with the diaphragm by intercostals. This holds true for both surfaces of the diaphragm. All viscera are innervated by two routes, either via afferents that follow a similar route to the spinal cord as afferents from somatic structures, or with autonomic efferents. Detailed study of the splanchnic nerves reveals that afferent fibres synapse with dorsal horn cells in laminae I and V. Most dorsal horn cells receiving visceral input also receive a somatic input. Visceral nociceptive afferent fibres are best described as such (rather than 'sympathetic afferents'). Sympathetic efferents may play an indirect role in nociception as described in the section above. Several mechanisms have been proposed for referred pain including branched primary afferents, reflex activation of nociceptors and perceptual projection. All may occur, but the most widely held view is that the mislocalisation results from sparse innervation of viscera and the convergence of afferent information from viscera and from superficial segmentally related tissue on to the same dorsal horn projection neurones. Referred pain is important in diagnosing the underlying disorder and should be distinguished from non-referred pain as one step in deciding appropriate pain therapies.
Central projection of nociceptive information Nociceptive information is transmitted to the brain stem and thalamus in the anterolateral (spinothalamic) tracts of the spinal cord on the opposite side to the stimulus. Some information, though inadequate to localise the source of a noxious stimulus, passes up ipsilateral tracts so that disruption of the anterolateral tracts (e.g. by cordotomy) is followed by a variable partial recovery of sensation. The ipsilateral tracts terminate in 'the intralaminar thalamus; the crossed tract axons separate into lateral and medial divisions, which terminate in the ventrobasal (lateral) nucleus and the posterior nuclear group, and the central lateral (medial) nucleus of the interlaminar complex and the nucleus submedius respectively. The lateral thalamic nuclei receive input from cells arising in lamina f (nociceptive specific) and V (WDR) with small receptive fields and project directly to the somatosensory cortex in a topographical arrangement. The medial nuclei receive their input from spinal cells located in deeper laminae VI, VII or VIII which have large receptive fields and project widely to the ipsilateral cortex and the frontal lobe. The brainstem reticular formation receives input from laminae V, VI, VII and VIII via the spinoreticular tract and makes bilateral contributions to the medial thalamic nuclei. The medial nuclei have connections with the frontal lobes. The frontal lobe is not concerned with the sensory-discriminative aspects of noxious stimuli (that is the role of the somatosensory cortex) but with the affective-motivational components of pain. 5
POST-OPERATIVE PAIN 29
Descending inhibition Electrical stimulation of several areas of the midbrain including the peri-aqueductal grey matter (PAG) and rostroventral medulla (RVM) inhibit dorsal horn noeiceptive neurones. The RVM receives input from the lateral and dorsolateral pontine tegmentum. Neurones in the RVM and pons project directly to the spinal cord and connect with neurones in laminae I, II and V in the dorsal horn through the dorsolateral funiculus. Many cells that originate in the pons contain noradrenaline whereas many cells projecting from the RVM are serotinergic, particularly the Nucleus Raphe Magnus (NRM). There are enkephalinergic inhibitory interneurones in the substantia gelatinosa. These are excited by the serotinergic cells and then inhibit nociception. Exogenous opioids mimic this effect on the dorsal horn neurones. Enkephalinergic cells are found also in the PAG and RVM, and opioids also act on these centres to modulate pain sensation. This is an extremely simple description. There are many other connections and many other amines and peptides released by neurones in the brain and spinal cord. Whilst the full story has yet to be elucidated, the information available at present can be used to develop better pain therapies.
Post-operative pain therapies It is clear from the above that the conduct of anaesthesia may affect subsequent pain sensation profoundly. The nociceptive barrage called surgery must be modified to prevent changes occurring in the dorsal horn. 2 It has been reported that small doses of opioid administered before noxious stimulation can suppress hyperexcitability, whereas larger doses of opioid are required to achieve the same response once hyperexcitability has become established. 12'13 Post-operative pain is not simply the sustained activation of pain pathways; it is the result of changes in the system, from transduction to perception. It is only recently that clinical implications for pain management of this 'plasticity' of the nervous system have been realised. 13 Studies have demonstrated that a decrease in requirement for post-operative analgesic medication follows the use of opioid pre-medication, local anaesthetic peripheral nerve blockade (prior to surgery), epidural or spinal anaesthesia and non-steroidal anti-inflammatory drugs (prior to surgery). In 1911 anaesthetists were told that 'inhalational anaesthesia puts asleep only a portion of the brain and is at best only a veneer' and that combining neural blockade with general anaesthesia protects the nervous system. ~4 Three quarters of a century later the neurophysiological basis for such comments has been described. 2 Post-operatively, meas.ures should be directed towards pain prophylaxis and the prevention of
pathological changes in the central nervous system. These can be: 1. Interruption of the flow of sensation, e.g. at a neuronal level by continuous epidural or spinal analgesia with local anaesthetic, or at a synaptic level by block of the neurotransmitters of the primary afferent nociceptor. 2. Prevention of hyperalgesia both peripherally, e.g. with non-steroidal anti-inflammatory drugs (NSAIDs), and centrally, e.g. by low-dose opioid therapy. 3. Activation of pain-modulating pathways, e.g. by psychological measures, or with stimulation-produced analgesia, e.g. transcutaneous electrical nerve stimulation. 4. Augmentation of pain-modulating pathways, e.g. by administration of exogenous substances acting on opioid, noradrenergic or serotinergic receptors. 5. Combination therapies which include elements of the above categories.
1. Interruption of sensation Total blockade of pain sensation after abdominal surgery is possible by continuous epidural blockade. However, central changes still occur and studies have revealed that the neuroendocrine response to surgery is not modified significantly by this technique. In addition this therapy requires special monitoring and nursing. It has been reported that continuous epidural analgesia reduces mortality in patients warranting admission to ICU post-operatively. 15 A conclusion of the most recent symposium on the influences of currently used anaesthetic procedures on surgical sequelae was that the effects of anaesthesia and analgesia on outcome are controversial. 16 If synaptic transmission between nociceptive afferents and dorsal horn neurones can be blocked, analgesia results. Fast transmission by excitatory amino acids is blocked by ~-opioid receptor agonists. The effects of such agents at different receptor subtypes (e.g. NMDA and quisqualate) suggest that new types of analgesic drugs can be developed. 6
2. Prevention of hyperalgesia Peripheral sensation can be reduced by good pain control, which defuses the effect of feed-forward sympathetic efferents. NSAIDs and steroids also reduce nociception at this level, as do bradykinin antagonists. 6 Wind-up has been discussed above. The interaction with prior depolarisation at the dorsal horn leading to this process can be abolished by small 'preventive' doses of opioids. Other NMDA antagonists, e.g. ketamine, can prevent wind-up. Prompt control of pain leading to lower dose requirements (e.g. with patient-controlled analgesia; PCA) can be explained by control of wind-up.
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CURRENT ANAESTHESIA AND CRITICAL CARE
3. Activation of pain-modulating pathways
Table - - Examples of different scales for pain measurement
Activation of descending inhibitory pathways is important in the response to placebo analgesics, which can be naloxone-reversible. Cognitive pain control techniques also act by this mechanism and so too rhay transcutaneous nerve stimulation and acupuncture.
0= 1= 2= 3= 4=
no pain Mild pain Moderate pain Severe pain Unbearable pain*
0 1 2 3 4
= = = = =
no pain Sometimes moderate pain Always moderate pain Sometimes severe pain Always moderate, sometimes severe pain. 5 = Discontinuation of therapy due to inefficacy
* This category frequently omitted
4. Augmentation of pain-modulating pathways Augmentation of the inhibitory pathways is extremely important and a major component of opioid analgesia occurs through this mechanism. Surgeons often express the fear that analgesia will mask signs of developing complications (e.g. biliary leak after cholecystectomy). It should be emphasised that opioids can prevent central sensitisation (pathological pain) and augment descending controls but they do not block physiological (incident) pain very effectively. For example, opioids administered for analgesia in patients with an acute abdomen alter physical signs in proportion to dosage, but have no effect on clinical diagnosis. 17
5. Combination therapy The major advances in post-operative pain treatment have involved combination therapies or 'balanced analgesia'. A combination of NSAID and opioid is very effective after surgery and combinations of epidural local anaesthetic and opioid are also effective. Recently, epidural local anaesthetics plus opioid have been combined with NSAID, resulting in complete pain relief at rest and very little pain on movement, as
Prevention of persistent post-surgical pain Not all post-operative pain resolves. Surgery may initiate on-going pain syndromes which can arise as a result of the interplay of nociception, neuropathy and environmental/psychological factors. Identified predisposing or risk factors include a genetic influence in neuroma formation, duration and severity of pain both before and after surgery, surgical technique and age. 3 Some data suggest that effective pain control is instrumental in preventing the development of persistent post-surgical pain syndromes.
Measurement of post-operative pain The monitoring of post-operative pain is also undergoing significant change. The rating scales used range from the bipolar pain/no pain responses through variations of ordered categorical scales (Table) to the 10cm visual analogue scale with 100 pain divisions. Pain rating scales may be applied at a particular time or are applied retrospectively. Excessively frequent
measurement of post-operative pain can, however, be counterproductive. There is now a trend away from simply examining pain or pain relief towards restoration of function along with analgesia. Thus more studies are being undertaken that consider pain both at rest and on movement, on objective measurement of the physiological response to pain therapies (e.g. nitrogen balance or respiratory function) and on rehabilitation measures (e.g. time to sit, stand or be discharged home). 15'16'18 Measures of outcome, in addition to audit of structure and process, will become increasingly important. The range of pain-controlling therapies currently used clinically has been reviewed recently by Mitchell and Smith. 2° The recent developments outlined above now need to be applied.
Conclusions An understanding of the neurobiology and pathophysiology of acute pain allows us to analyse the shortcomings of our present pain therapies. The information to improve our use of the drugs available at present exists but has yet to be widely implemented. New analgesics are being developed but it is likely that they too will be most effective when used in combination therapies.
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POST-OPERATIVE PAIN 11. Head H. On disturbances of sensation with especial reference to the pain of visceral disease. Brain 1893; 16:1-132 12. Wall PD. The prevention of post-operative pain. Pain 1988; 33:289-290 13. McQuay HJ, Dickenson AH. Implications of nervous system plasticity for pain management. Anaesthesia 1990; 45: 101102 14. Crile GW. Nitrous oxide anaesthesia and a note on anociassociation, a new principle in operative surgery. Surg Gynecol Obstet 1911; 13:170-173 15. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high risk surgical patients. Anesthesiology 1987; 66:729-736
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16. Covino BG. Influence of anaesthetic procedures on surgical sequelae. Acta Chir Scand 1989; 550 17. Zoltie N, Cust MP. Analgesia in the acute abdomen. Ann R Coll Surg 1986; 68:209-210 18. Kehlet H. Surgical stress: The role of pain and analgesia. Br J Anaesth 1989; 63:189-195 19. Chapman CR, Casey KL, Dubner R, Floey KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985; 22:1-31 20. Mitchell RWD, Smith G. The control of acute post-operative pain. Br J Anaesth 1989; 63:147-158