Researcher 2017;9(12) http://www.sciencepub.net/researcher

Pain Management in Hepatic Patients Following Abdominal Surgery

Prof. Dr. Laila Ali El-kafrawy, Dr. Mona Refaat Hosney and Michael Harby Habeeb

Anesthesiology and Intensive Care Department, Faculty of Medicine, Ain Shams University, Egypt [email protected]

Abstract: Pain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. [Laila Ali El-kafrawy, Mona Refaat Hosney and Michael Harby Habeeb. Pain Management in Hepatic Patients Following Abdominal Surgery. Researcher 2017;9(12):15-33]. ISSN 1553-9865 (print); ISSN 2163-8950 (online). http://www.sciencepub.net/researcher. 3. doi:10.7537/marsrsj091217.03.

Keywords: Pain; Management; Hepatic Patient; Abdominal Surgery

Introduction Pharmacokinetic investigations in a variety of Pain management in patients with cirrhosis is a chronic liver diseases without cirrhosis (e.g. difficult clinical challenge for health care carcinoma, schistosomiasis and viral hepatitis) suggest professionals, and few prospective studies have that in the absence of cirrhosis, impairment of drug offered an evidence-based approach. In patients with elimination is not sufficient to warrant reduction of end stage liver disease, adverse events from analgesics drug dosage. However, if cirrhosis is present, ‘safe’ are frequent, potentially fatal, and often avoidable. drug use requires an awareness of the possibility of Severe complications fromanalgesia in these patients multiple interactions between changes in hepatic and include hepatic encephalopathy, hepatorenalsyndrome, renal disposition and pharmacodynamics. (Morgan & and gastrointestinal bleeding, which can result in McLean 1995). substantial morbidity and even death. (Chandok & Over-the-counter analgesics, principally Watt 2010). acetaminophen and NSAIDs, are commonly used The effects of liver disease on pharmacokinetics medications worldwide. Acetaminophen is the most and pharmacodynamics are highly variable, and common cause of fulminant hepatic failure in the difficult to predict as the mechanisms of these effects United States, creating the perception that it may be are not well understood. dangerous in patients with chronic liver disease. In Four different theories have been proposed to such patients, the half-life of oral acetaminophen is account for the effects of chronic liver disease with double that in healthy controls, but hepatic injury and cirrhosis on hepatic drug elimination: the sick cell renal injury are rare when the dosage is limited to less theory; the intact hepatocyte theory; the impaired drug than 4g/d. uptake theory; and the oxygen limitation theory. Like anti-inflammatory medications, opioids can In cirrhosis, drug glucuronidation is spared have deleterious effects in patients with cirrhosis. If relative to oxidative drug metabolism; however, in opiates are required for pain control, lower doses advanced cirrhosis this pathway may also be impaired and/or longer intervals between doses are needed to substantially. There is evidence that in cirrhosis other minimize risks. Hydromorphone and fentanyl may be conjugation pathways may also be impaired to the better choices. variable degrees. Growing evidence suggests that In general, our recommendation (expert opinion) biliary drug excretion is impaired in cirrhosis. for long-term acetaminophen use in cirrhotic patients A major finding which has emerged in recent (not actively drinking alcohol) is for reduced dosing at years is that, even with moderate degrees of hepatic 2 to 3 g/d. For short-term use or 1-time dosing, 3 to 4 impairment, there is a decrease in clearance of drugs g/d appears to be safe; however, with the new FDA or active metabolites normally cleared by the kidney. recommendations, a maximum dosage of 2 to 3 g/d is Neither serum creatinine levels nor creatinine recommended. NSAIDs and opioids may be used at clearance are useful markers of the renal dysfunction reduced doses in patients with chronic liver disease associated with cirrhosis. Both may greatly without cirrhosis. Patients with cirrhosis have fewer overestimate renal function in patients with cirrhosis analgesic options. NSAIDs should be avoided in those due to increased fractional renal tubular secretion of with both compensated and decompensated cirrhosis, creatinine. primarily because of the risk of acute renal failure due

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to prostaglandin inhibition. Opiates should be avoided neuraxial catheter during sustained anticoagulation or used sparingly at low and infrequent doses because (particularly with standard unfractionated heparin or of the risk of precipitating hepatic encephalopathy. low molecular weight heparin). (Horlocker 2011). Patients with a history of encephalopathy or substance Physiology of pain abuse should not take opioids. When appropriate, Pain: anticonvulsants and antidepressants are options The international association of pain defines pain worthy of exploration in chronic neuropathic pain as an unpleasant sensory and emotional experience management in patients with advanced liver disease. associated with actual or potential tissue damage, or Diligent follow-up for toxicity, adverse effects, and described in terms of such damage. There is an complications is necessary. (Mayo ClinProc, 2010). inherent concept in all definitions of pain, which is Whether or not neuraxial anesthesia should be that the pain always has a major subjective component performed in hepatic patients is a matter of and it includes both a physiologic sensation and an considerable debate. The hypothesis that epidural emotional reaction to that sensation. In some cases, analgesia would improve liver blood flow, thus there may be no tissue injury; but the pain is no less leading to better outcome has been supported by many "real" (Kanner 2003). studies using animal models. Terms used in pain: Obviously, lumbar epidural blocks have either no Allodynia: influence or a negative effect on liver perfusion. A Pain due to a stimulus which does not normally recent study reported augmented liver perfusion under provoke pain. a thoracic epidural regimen. In two other papers, Analgesia: thoracic epidural analgesia lead to reduced hepatic Absence of pain in response to stimulation which blood flow that was further decreased when would normally be painful. catecholamines were administered to increase blood Central pain: pressure. With respect to the postoperative course, Pain initiated or caused by a primary lesion or epidural analgesia seems favorable because of the dysfunction in the central nervous system (Kanner reduction in pain, morphine consumption, and the fact 2003). that it may allow earlier extubation even after liver Dysaesthesia: transplantation. It is well known that epidural An unpleasant abnormal sensation, whether anesthesia leads to vasodilatation and increased fluid spontaneous or evoked (Kanner 2003). application in hepatic surgery. Even if epidural Hyperalgesia: anesthesia in patients with CLD undergoing minor Increased response to a stimulus which is abdominal surgery might exert beneficial effects on normally painful. the haemostatic system, care should be taken with Hyperesthesia: postoperative liver dysfunction after hepatic resection. Increased sensitivity to stimulation, excluding First, local anesthetics are metabolized hepatically and special senses (Kanner 2003). plasma concentrations might increase significantly in Hyperpathia: these patients. Second, a high prevalence of A painful syndrome characterized by an haemostatic abnormalities is found in patients abnormally painful reaction to a stimulus, especially a undergoing major liver resection while receiving repetitive stimulus, as well as an increased threshold epidural analgesia. (Kanner2003). The same is true for subcostal hypoalgesia: transversusabdominis plane blocks or the installation Diminished pain in response to a normally of a catheter into the musculo-fascial layer before skin painful stimulus. closure. (Friedman, 2010). Hypoesthesia: The actual incidence of neurological dysfunction Decreased sensitivity to stimulation, excluding resulting from hemorrhagic complications associated the special senses (Kanner2003). with neuraxial block is unknown. Neuralgia: Although the incidence cited in the literature is Pain in the distribution of a nerve or nerves. estimated to be 1 in 150 000 epidural and 1 in 220 000 Neuritis: spinal anesthetics, recent surveys suggest that the Inflammation of a nerve or nerves (Kanner frequency is increasing and may be as high as 1 in 2003). 3000 in some patient populations. Overall, the risk of Neuropathic pain: clinically significant bleeding increases with age, Pain initiated or caused by a primary lesion or associated abnormalities of the spinal cord or vertebral dysfunction in the nervous system. column, the presence of an underlying coagulopathy, Neuropathy: difficulty during needle placement, and an indwelling

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A disturbance of function or pathological change response thresholds and persistent discharge without in a nerve: in one nerve, mononeuropathy; in several rapid adaptation and are associated with small nerves, mononeuropathy multiplex; if diffuse and receptive fields and small afferent nerve fiber endings bilateral, and polyneuropatyhy (Kanner 2003). (Waugh and Grant 2001). Nociceptor: a) C-Polymodal receptors (C-PMNs): A receptor preferentially sensitive to a noxious These are abundant non-myelinated C fibers stimulus or to a stimulus which would become which respond to all 3 noxious stimuli, i.e., thermal, noxious if prolonged. mechanical and chemical (Sharpe et al., 1996). Noxious stimulus: b) A-Mechano-Heat Receptors (AMHs): A noxious stimulus is one which is damaging to These respond to mechanical and thermal normal tissue and maybe chemical, thermal or stimuli, and the afferent stimuli travel in A-delta (Ay) mechanical (Kanner 2003). fibers (Waugh and Grant 2001). Pain threshold: c) High-Threshold mechanoreceptors: The least experience of pain which a subject can These only respond to intensive mechanical recognize. stimuli. The afferent stimuli travel in AB fibers Pain tolerance level: (Waugh and Grant 2001). The greatest level of pain which a subject is d) Muscle nociceptors: prepared to tolerate. These are thought to be the free nerve endings Parasethesia: found in the connective tissue between muscle fibers An abnormal sensation, whether spontaneous or and in tendons and blood vessels (Sharpe et al., evoked. 1996). Peripheral neuropathic pain: e) Silent nociceptors: Pain initiated or caused by a primary lesion or These C fiber afferent do not fire in response to dysfunction in the peripheral nervous system (Kanner any noxious stimuli in normal tissue. In the presence 2003). of inflammation, they become sensitized, even to the Types of pain: point of being spontaneously active and Two types of pain are usually described: mechanosensitive. As a consequence, the inflamed Sharp pain: it is often described as a pricking tissue becomes very tender and hurts with minimal sensation, can be accurately localized and rapidly movement (Waugh and Grant 2001). conducted. It is felt mostly in the skin and usually Receptor sensitization: does not outlast the stimulus. Repeated application of noxious stimuli to Dull pain: it is usually preceded by sharp pain. It nociceptors will usually result in alterations in their is felt both in skin and deeper tissues; it is diffuse and thresholds and responses. The nociceptor may become slowly conducted and outlast the provoking stimulus damaged and stop functioning if the stimuli were (Kanner 2003). intense. Sometimes repeated stimulation result in Acute pain signifies the presence of a noxious fatigue of the nociceptor. However the most common stimulus that produce actual tissue damage or phenomenon is that of sensitization (Guyton 2006). possesses the potential to do so. The presence of acute With repeated noxious stimulus, most pain implies a properly working nervous system and is nociceptors start responding to lower intensity associated with autonomic hyperactivity like stimulus, (decreased threshold) and produce larger hypertension, tachycardia, sweating and response than initially to the same stimulus. This vasoconstriction (Macintyre et al., 2007). explains at least partially the hyperalgesia apparent On the other hand, chronic pain implies the after burns and other noxious stimuli (Dostrovsky absence of a threat tissue damage, but the patient 1990). describes the experience " in terms of such damage ", 2. Afferent nerve fibers: Function of the nervous system become reorganized After the activation of nociceptors, impulses are with the potential for spontaneous and atopic nerve conducted along specific nerve fibers. These can be excitation. Autonomic hyperactivity is absent. Pain is broadly classified into low and high threshold primary seemed to be chronic when it persists beyond 3-6 afferents. Low threshold afferents are myelinated months (Macintyre et al., 2007). fibers with specialized nerve endings that convey I- Peripheral nervous system innocuous sensations such as light touch, vibration, 1. Nociceptors pressure (all Aβ) and propriocepeption (Aα). High Stimuli generated from thermal, mechanical, or threshold afferents are thinly myelinated (AY) or chemical tissue damage activate nociceptors, which unmyelinated (C) fibers located in the dermis and are free nerve endings. In contrast to other special epidermis, which convey pain and temperature somatosensory receptors, nociceptors exhibit high (Guyton 2006).

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The AY and C fibers have their cell bodies in the The C fibers are the smallest of the peripheral dorsal root ganglion. From there, they project to the nervous system, they are unmyelinated, with a dorsal horn of the spinal cord. diameter ranging from 0.5 to 1 µm, and their Because of this double system of pain conduction rate is from 0.2 to 1.5 m/sec. About 50% innervations, a sudden onset of noxious stimulus gives of C-fibers respond to pain, whereas the remaining a double pain sensation: a fast sharp pain transmitted 50% respond to mechanical stimuli (Almeida et al., by AY fibers followed by a second or so later by a 2004). slow, chronic burning pain transmitted by C fibers. Although both Aõ and C fibers transmit When type C fibers are blocked without blocking the nociceptive impulses, the characteristics of the AY fibers by low concentration of local anesthetic, the sensations carried are different. Aõ fibers carry slow chronic burning type of pain disappear. (Guyton primarily sharp pain, whereas C fibers carry dull pain. 2006). For example, after a pin -prick, an immediate sharp Three specific types of nerve fibers have been pain is mediated by fast -conducting myelinated Aõ identified (A, B and C) as shown in (table 1). fibers (called; first pain). This is followed by a dull The classification is based on the diameter of the pain, which is mediated by C fibers (called; second fiber and the speed of conduction of the impulse. pain) (Almeida et al., 2004). The A-fibers, which are the largest and conduct Although pain result from damage to these free impulses most rapidly, are subdivided into four nerve endings, in reality the pain is a result substances groups: alpha, beta, gamma and delta, in order of released by damaged tissues: prostaglandins, decreasing size. The largest A fibers (alpha) are histamine and peptides. These activate receptors myelinated fibers with a diameter ranging from 12 ti located on the nerve endings (Guyton 2006). 20 µm. They conduct impulses at a rate of 70 to 120 II- Central nervous system m/sec. and subserve proprioception and somatic motor 1. The spinal cord: function. The spinal cord consists of grey matter and white matter. Table (1): Shows Characteristics of nerve fibers The white matter contains ascending and (Dwarakanath 1991). descending fibers, the grey matter contains cells and Diameter Conduction central terminals of primary afferents from the Type Function µm velocity (m/s) periphery. (dull) Pain, The dorsal horn is divided into 6 layers (laminae) C 1 0.2-1.5 mechanical stimuli and processes sensory information. Lamina (I) IS the Preganglionic, most dorsal and is a thin layer of large cells, together B 1 3-14 autonomic with small inhibitory interneurons. The axons from the Sharp Pain, large cells form part of the spinothalamic tract Aᵹ mechanical and 1 5-15 (Waugh and Grant 2001). thermal The second layer is lamina (II) or the Touch and muscle "substantiagelatinosa". It is where most of the A 4 15-40 tone modulation and sensory processing occurs, so, many Touch, of the cells are inhibitory but excitatory cells exist as Aß 8 40-70 proprioception well. Motor, Aα 13 70-120 This region is believed to control the proprioception "connectivity" of the other laminae in the dorsal horn. Together, laminae I & II are known as the superficial The Aß fibers also are myelinated (diameter of 5 dorsal horn (lamina terminalis) and receive input from to 12 µm) and conduct at a rate of 30 to 70 m/sec. C and Aᵹ fibers. Functionally, they receive input from These myelinated fibers which are located in skin, nociceptors (high threshold C and Aᵹ fibers) and joints, muscles and viscera respond to mechanical contain cell that are nociceptive specific (NS) stimuli, such as touch, pressure, proprioception and (respond only to noxious stimuli) or wide dynamic motor function. The Aõ fibers are the thinnest range (WDR) (respond to both innoxious and noxious myelinated fibers in the A group, about 75% of them stimuli) (Haines and Lancon 2003). respond to mechanical and thermal stimulation and the Laminae III & VI receive input from the remaining 25% respond to noxious stimuli (Almeida cutaneous Aβ non-nociceptive afferents and contains et al., 2004). cells with low-threshold (LT) receptive fields that B-fibers are Preganglionic autonomic fibers, respond to innoxious sensations. which conduct both sympathetic and parasympathetic Some lamina V cells are WDRs that receive impulses. input from both low-threshold (Aβ) sensory fibers and

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high-threshold (C, Aᵹ) fibers as their dendrites project of neurons in the various thalamic nuclei (Almeida et dorsally into laminae I & II (Almeida et al., 2004). al., 2004). The dorsal horn is not just a relay station for the transmission of innoxious and noxious messages. It Table (2): Comparison of central pathways for pain has an important role in modulating pain transmission transmission, (Kandel et al., 2000) through spinal and supraspinal mechanisms. These Direct (fast) Indirect regulatory circuits involve primary afferents, spinal Tract Lateral-STT Lateral-STT interneurons and descending fibers. (Almeida et al., Lamina I, IV, V, Origin Lamina I & IV, V 2004). (and VII, VIII) 2. The supraspinal pathways of pain Somatotropic Yes No a) The spinothalamic tract organization The major ascending pain pathway is the Body Contralateral Bilateral spinothalamic tract which lies anterolaterally in the representation white matter of the spinal cord (figure 2). This tract Synapse in can be divided as lateral (neospinothalamic) tract and reticular No Yes medial (paleospinothalamic) tract. (Kandel et al., formation 2000). Hypothalamus The lateral spinothalamic (neospinothalamic) Sub-cortical Limbic system None tract is composed of long, relatively thick fibers (Aβ) targets Autonomic that conduct rapidly and projects to the ventral centres Intra-laminar posterolateral nucleus (VPLN) of thalamus. In the Ventral Thalamic nuclei VPLN of thalamus, second order neurons synapse posterolateral nucleus Other midline with third order neuron that project to the (VPLN) somatosensory cortex (Morgan et al., 2006). nuclei Parietal lobe (SI This lateral pathway is concerned with rapid Cortical location Cingulate gyrus transmission of discriminative aspects of pain, such as cortex) location, intensity, and duration (Morgan et al., 2006). Discriminative Affective-arousal The medial spinothalamic (paleospinothalamic) Role pain (quality components of intensity, location) pain tract is composed of thin fibers, some long and some Temperature short, that project to the reticular formation, Other functions Simple touch periaqueductal gray (PAG), hypothalamus, and medial and intralaminar thalamic nuclei. The fibers then make contact with neurons that Role of cerebral cortex in pain: connect with limbic structures and diffuse projections Little is known concerning the role of the cortex to many other parts of the brain (Raj et al., 1996). in pain. Although it was believed that the perception The medial spinothalamic tract is responsible for of pain took place at the thalamic level; most mediating the autonomic, endocrine and unpleasant researchers today believe that pain perception occurs emotional aspects of pain that make the organ to take in the cortex. In recent years, a number of studies have appropriate action when challenged (Morgan et al., described the existence of nociceptive neurons 2006). primary sensory cortex (Guyton 2006). b) Alternate pain pathway However lesions to primary somatosensory The spinoreticular tract mediates arousal cortex in humans rarely produce a significant or autonomic responses to pain while the lasting reduction in chronic or evoked pain. It is likely spinomesencephalic tract may be important in that the cerebral cortex has multiple representations of activating anti-nociceptive, descendig pathways pain and thus it is difficult to abolish pain perception (Kandel et al., 2000). with a single lesion (Guyton 2006). Thalamo-cortical interactions: Central processing of visceral and deep pain It is well known that each region of the thalamus inputs: receiving inputs from pathways of the ventral Nociceptive inputs from the viscera, muscle and quadrants of the spinal cord, projects to two regions of other deep structures converge onto neurons that also the sensory cerebral cortex namely; primary and receive cutaneous nociceptive inputs (Guyton 2006). secondary somatosensory cortices (SI & SII). Also the There appear to be no neurons, or very few, that thalamus receives inputs from several cortical regions, respond exclusively to noxious inputs arising from these corticothalamic projections are quite extensive visceral structures (e.g. uterus & cervix). These and play a significant role in modifying the behavior findings provide an explanation for the fact that visceral pain is frequently referred to a different site.

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The central nervous system has no way of It is a biogenic amine which is closely related to determining the source of noxious inputs if the same noradrenaline and has a similar action to dopamine. In neurons receive inputs from multiple sites and vertebrates, octopamine also replaces norepinephrine therefore the input is referred to the more commonly in sympathetic neurons with chronic use of activated cutaneous site. Pain of cutaneous origin does monoamine oxidase inhibitor (Haller et al., 2005). not usually feel the same as visceral pain; probably There are at least two potential types of due to the fact that it results from activation of a neuromodulation: different, although overlapping, group of neurons In the first, neuromodulators are released from whose responses are characterized by different firing neurons glia, or true secretory cells to amplify or patterns (Guyton 2006). dampen, that is, set the tone of local synaptic activity Neuromodulators: by altering the effectiveness of a neurotransmitter. A neuromodulator is a substance other than a Unlike neurotransmitter, neuromodulators do not neurotransmitter, released by a neuron at a synapse need specific receptors; they might affect and conveying information to a region of neurons, neurotransmitter synthesis, release, receptor either enhancing or dampening their activities. In interactions, reuptake or metabolism (Guyton 2006). contrast, neurotransmitters only convey information In the second, a neuromodulator is released between two neurons. either within the brain or from other parts of the body Neuromodulators may alter the output of a to act directly on a large number of neurons at some physiological system by acting on the associated distances from the release site. inputs. Such effects could be quite-long- lasting, helping A neuromodulator is a relatively new concept in to influence either baseline activity or response to the field anad it can be conceptualized as a other neuronal input (Guyton 2006). neurotransmitter that is not reabsorbed by the pre- Pain modulation synaptic neuron or broken down into a metabolite do Gate control theory of pain: not need specific receptors. Such neuromodulators end The transmission of information from primary up spending a significant amount of time in the afferents to secondary neurons in the CNS is subject to cerebrospinal fluid and influencing (or modulating) "gating" (modulation). the overall activity level of the brain (Kandel et al., Nociceptive sensory information is gated in the 2000). substantiagelatinosa of the spinal cord. Gating is of Neuromodulation also refers to a medical two kinds: procedure used to alter nervous system function for Local: segmental antinociception. relief of pain. For this reason, some neurotransmitters Widespread: supraspinalantinociception which are also considered as neuromodulators. Example of utilizes descending pathways from the brainstem. Neuromodulators in this category are serotonin and The Gate control theory was devised by Patrick acetylcholine (Stern et al., 2007). Wall and Ronald Mellzack in 1965. This theory states Types of neuromodulators: that pain is a function of the balance between the Opioid peptides - these substances block nerve information travelling into the spinal cord through impulse generation in the secondary afferent pain large nerve fibers and information travelling into the neurons. These peptides are called opioid peptides spinal cord through small nerve fibers, there should be because they have opium-like activity. The types of little or no pain. However, if there is more activity in opioid peptides are: small nerve fibers, then there will be pain.  Endorphins So this theory assumes that the various relay  Enkephalins stations in the nervous pathway of pain act as gates  Dynorphins that can be opened or closed. The most important Substance P: gates are located at the substantiagelatinosa of Rolandi It is a short-chain neuro-polypeptide that functios and at the thalamus (-spinal and thalamic gates as a neurotransmitter and as a neuromodulator. respectively). A 3rd gate may also be located in the It belongs to the tachykinin neuropeptide family. reticular formation. The endogenous receptor for Substance P IS At the spinal gate, pain transmission can be blocked neurokinin-1 receptor. In the central nervous system, by: substance P has been associated in the regulation of a. Collaterals from the thick myelinated fibers mood disorders, anxiety, stress, reinforcement, in the dorsal column. neurogenesis, respiratory rhythm, neurotoxicity, b. Descending fibers from certain higher centers nausea/ emesis and pain (Park et al., 2003). (- corticofugal or centrifugal control). Such block Octopamine: occurs by presynaptic inhibition, and the same mechanism is also believed to occur at the thalamic

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gate and the reticular formation (through the so that cognitive processes can rapidly and directly corticofugal control). modulate neural transmission in the dorsal horn The gate theory explains the pain relief achieved (Barclay L and Hien TN; 2006). by counter-irritants (e.g. liniments and mustard C. Concept of a central control trigger: plaster), skin rubbing, and by shaking the painful part It is apparent that the influence of cognitive (all these methods are supposed to stimulate the central control processes on spinal transmission is mechanoreceptors that activate the neurons in the mediated through the gate control system. Whereas dorsal column, the collaterals of which relieve pain) some central activities, such as anxiety or excitement, (Kandel et al., 2000). may open or close the gate for all inputs from any part Brain activities subserving attention, emotion and of the body, others obviously involve selective, memories of prior experience, exert control over localized gate activity. sensory input via descending efferent fibers. This Mellzack and Wall (1965) have therefore control of spinal cord transmission by the brain is proposed that there is a ventral mechanism which they exerted through system: have called the central control trigger, which activates A. Brainstem projections: the particular selective brain processes. One of the mostpowerful descending modulating These brain activities do not give rise to sensory systems, exerting powerful inhibitory control over experience but instead act by way of central control information projected by spinal transmission, is efferent fibers on gate control system. Part of their special neurons in the periaqueductal and function, could be to activate selective brain processes periventricular grey matter in the midbrain (Kandel et such as memories of prior experience and preset al., 2000). response strategies that influence information which is These neurons descend in the dorsolateral still arriving over slowly conducting fibers or is being funiculus to different levels of the spinal cord and transmitted up more slowly conducting pathways. make connections with laminae I, II and IV. This Postoperative pain descending inhibitory projection is itself controlled by It is advocated that for success in treatment and multiple influences, including somatic, visual and clinical diagnosis of pain needs to expand the concept auditory projections to the midbrain reticular of a pathologic lesion to include psychological; formation. Higher brainstem areas are involved in emotional, intellectual, cultural, and societal descending control (Kandel et al., 2000). components and to do so is to acknowledge that even It has been shown convincingly that electrical when an anatomic-physiological disorder cannot be stimulation of periaqueductal and periventricular grey cured, and the associated pain remains intractable, matter produces profound analgesia without affecting psychosocial aspects of the lesion can be addressed, motor function. This is achieved by powerful often with considerable success, so that suffering can descending inhibitory action that totally blocks the be lessened or even eliminated, and patients can return passage of nociceptive impulses in the dorsal horn. to the normal activities of daily living in spite if an One of the ways of this work is by liberating otherwise untreatable lesion (Haljamen and Warren endogenous opiate peptides: encephalin, endorphins, 2003). dynorphins (Dwarakanath 1991). It is well known that the experience of pain is B. Cortical projections: exceedingly complex. It strikes a patient as the final The somatosensory cortex is not essential to pain common pathway that originates in a complexity of perception, but it is useful in regulating subcortical anatomical, physiological, psychological, and activity related to pain through complex reflexes and sociological causes, so that a particular level of serves as a discriminative function. Impulses from the suffering often does not correspond in any periphery that reach the cerebral cortex undergo straightforward way or any specific level of incredible modulation in the process of transmission physiologic anatomic pathology as such. It is difficult (Mellzack 1986). to quantify the contribution of these elements in the Fibers from the whole cortex, particularly the overall experience of acute postoperative pain frontal cortex, project to the reticular formation. observed in an individual patient. That is to say there Cognitive processes such as past experience and is a great variability in degree of pain perceived in attention which are subserved by cortical neural response to tissue damage (Haljamen and Warren activity are able to influence spinal activities by way 2003). of the reticulospinal projection system (Mellzack A revolution in the management of acute 1986). postoperative pain has occurred during the past two Cognitive processes can also influence spinal decades. Widespread recognition of the under gating mechanisms by means of pyramidal (or cortico- treatment of acute pain following surgery by spinal) fibers. These are large, fast-conducting fibers clinicians, economists, and health policy exerts has led

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to the development of a national clinical practice The re-interpretation of a past painful event may guideline for acute pain management by the agency alter the current implications of the event. for health care quality and research of the U.S. Positive and negative feelings: department of health and human services (Nielsen et When the patient anticipates great benefit from al., 2007). the proposed operation, may be more willing to trade Effective control of postoperative pain remains short-term discomfort for long-term gain. Whereas the one of the most important and pressing issues in the surgery involves mutilation, confirmation of a poor field of surgery with significant impact on our health prognosis or no perceived gain in the patient's mind, care system, because of the following: the additional anxiety may compound the difficulty of a. Most of the hundreds of millions of people providing postoperative analgesia (Mitchell and smith worldwide who undergo surgeries each year 1989). experience postoperative pain of variable intensity. Effect of Surgical and Anesthetic Management: b. In too many patients the pain is treated in Other factors that influence postoperative pain adequately, causing them needlessly suffering and are the surgical and anesthetic management, including may develop complications as an indirect consequence preoperative preparation of the patient, operation and of the pain. anesthetic technique and postoperative care. The skill c. Analgesic modalities, if probably applied, of surgeon and extent of the operative procedure help can prevent or at least minimize the needless suffering to determine the degree of surgical trauma, which in and complications (Alan et al., 1983). turn, partly determines the degree of postoperative There are many reasons why postoperative pain pain and complications. Similarly, the quality of the should be effectively treated, aside from alleviating a pre-anesthetic, intra-anesthetic and post-anesthetic patient's discomfort. Adverse effects of uncontrolled care influences the incidence and intensity of postoperative pain are impairing pulmonary functions, postoperative pain, both directly and indirectly gastrointestinal motility, cardiovascular instability and (Macintyre et al., 2007). prolonged decumbency with increased risks of deep Traumatic tracheal intubation and generalized venous thrombosis. muscle pain consequent to succinylcholine-induced Yet, it is often inadequately treated for several muscle spasm contribute directly to postoperative reasons: discomfort. Inadequate muscle relaxation and other a. Medical personnel often do not completely problems that prolong the operation contribute understand the pharmacodynamics of the analgesics indirectly by increasing the degree and duration of they prescribe. surgical trauma (Macintyre et al., 2007). b. There is exaggerated concern about addictive Nature and Pathophysiology of postoperative pain potential of analgesic medications. Surgical trauma produces local tissue damage c. Medical personnel are often unaware of that evokes nociceptive afferent activity which travel many options for treating postoperative pain aside back to the spinal cord. Action potentials also travel from conventional systemic medication. antidramatically, by axon collaterals into the Thompson at 1981 has identified four components to surrounding vascular bed to release substance P which this: is proposed to cause vasodilatation and increase 1. Behavioral control: vascular permeability that result into local edema and This describes any maneuver which the patient consequent release of algogenic substances and of a can use to decrease the perception of pain as; barrage of noxious stimuli, which are transduced by relaxation or breathing exercises or provision of nociceptors into impulses that are transmitted to patients controlled analgesia device. neuraxis by Aᵹ and C fibers. 2. Cognitive control: Algogenic substances such as potassium and This comprises the alteration of pain by thought hydrogen ions, lactic acid, serotonin, bradykinin and processes. These can act both to reinforce the pain prostaglandins stimulate and sensitize nociceptors that (e.g. by concentration on or reinterpretation of pain) or persist after the operation causing (hyperalgesia). decrease the pain (e.g. by denial, dissociation and Note also that nor-adrenaline release may distraction). increase the nociceptive sensitivity, further increasing 3. Information: afferent input to the spinal cord and initiating reflex Provision of adequate information reduces the increase in the sympathetic activity that result into uncertainty, and therefore the distress of a painful vasoconstriction, local tissue ischemia, increased experience. It familiarizes the patient with an hydrogen ion concentration further increase in unaccustomed experience. nociceptor sensitivity. On reaching the dorsal horn, 4. Retrospection: nociceptive impulses are subjected to modulating influences, which, together with other factors

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determine their further transmission. Some immune responses as granulocytosis, reduction in nociceptive impulses pass to anterior and anterolateral chemotaxis, increases in phagocytic activity and horns of the spinal cord to provoke segmental reflex decreases in T & B-lymphocytes and monocytes responses, while others pass to higher parts of functions (Bardiau et al,2003). neuraxis provoking suprasegmental and cortical Cortical response: responses (Turk and Melzack 2001). These occur in awakeunanaesthetized individual. Segmental reflex response: They are provoked by nociceptive impulses that reach Associated with surgery, include a marked highest parts of the brain, in which they activate increase in skeletal muscle tension, with a complex systems concerned with integration and concomitant decrease in chest wall compliance. These perception or with recognition of the sensation of pain, responses also initiate positive feedback loops that and also provokesmotor responses as well as anxiety generate nociceptive impulses from the muscles. and apprehension, which greatly enhances the Stimulation of sympathetic neurons causes increased hypothalamic response. Cortisol and catecholamine in heart rate and stroke volume, and thus increase in secretion in response to anxiety might even exceed the cardiac work and myocardial oxygen consumption and hypothalamic response provoked directly by concomitant decreased tone of gastrointestinal and nociceptive impulses. Moreover, anxiety and urinary tracts. The massive nociceptive barrage emotional stress can cause cortically induced generated by the operation also sensitizes dorsal horn increased blood viscosity and clotting, fibrinolysis and wide-dynamic-range neurons, interneurons and flexor platelet aggregation (Werner et al., 2002). motor neurons and thus reduces their thresholds and Responses during the operation: markedly increase their excitability both ipsilateral Unless excessive concentrations of inhalational and contralateral to the site of operation (Bardiau et agents or anesthetic doses of narcotics are used, the al., 2003). sympathetic, neuroendocrine and biochemical This sensitization persists for days after the responses provoked by injury-induced nociceptive operation and is in part responsible for the tenderness, input are reduced only slightly or not at all. This lack hyperalgesia, allodynia and the abnormal reflex of depression or elimination of reflex responses during responses that cause brief bouts of severe skeletal general anesthesia is often reflected by increase in muscle spasm that in turn produce excruciating pain cardiac output and blood pressure, even by cardiac (Bardiau et al., 2003). arrhythmia provoked by intense noxious stimulation, Supra segmental reflex response: they are also reflected by all the biochemical changes Nociceptive input to cardiovascular and characteristic of the stress response (Werner et al., respiratory control centers in the medulla oblongata 2002). that results in marked increase in general neural Responses in the postoperative period: sympathetic tone with further increase in cardiac Postoperatively, when the effects of surgical output, blood pressure, cardiac workload, metabolism anesthesia disappear, the patient's injury persists and and oxygen consumption, Nociceptive input to algogenic substances continue to be liberated. These hypothalamic centers such as autonomic and neuro- substances continue to sensitize nociceptors, so that endocrine control centers that result in marked tenderness ensues and innocuous stimulus such as increase in secretion of catabolic hormones as, touch produces pain. Such pathophysiologic changes Catecholamines, Cortisol, ACTH, ADH, Glucagon are greatly enhanced by sympathetic hyperactivity and and Aldosterone and concomitant decrease in consequent liberation of norepinephrine, which secretion of anabolic hormones an Insulin and sensitizes nociceptors and damaged nerve membrane. Testosterone. Moreover, sensitization of dorsal horn neurons, These endocrine changes produce a number of interneurons and flexor motor neurons persists for metabolic effects including increases in blood glucose, days after the operation (Werner et al., 2002). plasma cyclic AMP, free fatty acid, ketone bodies and In operations involving abdominal or thoracic blood lactate levels as well as an increase in general viscera, the total pain experience is produced by input metabolism and oxygen consumption. Such endocrine from three sites of injury: the skin, the deep somatic and metabolic changes result in substrate mobilization structures and the involved viscus or viscera. The from storage sites to central organs and the cutaneous component, results from liberation of traumatized tissues and ultimately produce a catabolic algogenic substances and from damaged cutaneous state with negative nitrogen balance. The degree and nerves. Pain is sharp, localized and often accompanied duration of these endocrine and biochemical changes by burning sensation. The deep somatic component, are related to the degree and duration of tissue results from liberation of algogenic substances and damage. The trauma of surgery also decreases the from consequent lowering of nociceptive threshold, as patient's immunocompetance including nonspecific well as, from damaged nerve axons in the fascia,

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muscle, pleura, or peritoneum. Pain is diffuse aching Opioids undergo varying degrees of phase 1 and discomfort felt either locally or in area of reference or 2 metabolism. Phase 1 metabolism usually precedes both. The visceral component of pain results from phase 2 metabolism, but this is not always the case. pathophysiology inherent in the surgical disorder, and Both phase 1 and 2 metabolites can be active or also from surgical trauma of the viscus that often inactive. The process of metabolism ends when the cause persistent nociceptive input. Pain is dull, aching, molecules are sufficiently hydrophilic to be excreted diffuse and felt locally or in area of reference or both from the body. (Totah et al., 2004). (Werner et al., 2002). In fact, active metabolites may be more potent Major joint operations entail massive nociceptive than the parent compound. Thus, although metabolism input from the richly innervated joint tissues that is ultimately a process of detoxifications, it produces produce continuous deep somatic pain and severe intermediate products that may have clinically useful reflex spasm of muscles supplied by the same and activity, be associated with toxicity, or both. adjacent spinal cord segments supplying site of (Mercadante 2000). surgery (Werner et al., 2002). Metabolic pathways: Parenteral and oral analgesics in hepatic patient Opioids undergoes phase 1 metabolism by the Pain management in hepatic patient using opioid CYP pathway, phase 2 metabolism by conjugation, or analgesics: both. Phase 1 metabolism of opioids mainly involves Opioids are a cornerstone of the management of CYP39A4 and CYP2D6 enzymes. The CYP3A4 cancer pain and postoperative pain and are used enzyme metabolizes more than 50% of all drugs; increasingly for the management of chronic noncancer consequently, opioids metabolized by this enzyme pain. (World Health Organization 1996) have a high risk of drug-drug interactions. Opioid metabolism: The CYP2D6 enzyme metabolizes fewer drugs Underlying the metabolism of opioids is of great and therefore is associated with an intermediate risk of practical importance to primary care clinicians. Opioid drug-drug interactions. Drugs that undergo phase 2 metabolism is a vital safety consideration in older and conjugation, and therefore have little or no medically complicated patients, who may be taking involvement with the CYP system, have minimal multiple medications and may have inflammation, interaction potential. (Quang-Cantagrel et al., 2000). impaired renal and hepatic function, and impaired PHASE 1 metabolism. immunity. Chronic pain, such as lower back pain, also Phase 1 metabolism typically subjects the drug to occurs in younger persons and is the leading cause of oxidation or hydrolysis. It involves the Cytochrome disability in Americans younger than 45 years. In P450 (CYP) enzymes, which facilitate reactions that younger patients, physicians may be more concerned include N-, O-, and S-dealkylation; aromatic, with opioid metabolism in reference to development aliphatic, or N-hydroxylation; Noxidation; of tolerance, impairment of skills and mental function, sulfoxidation; deamination; and dehalogenation. adverse events during pregnancy and lactation, and (Crettol et al., 2006). prevention of abuse by monitoring drug and The CYP3A4 enzyme is the primary metabolizer metabolite levels. (American Pain Society 2004). of fentanyl and oxycodone, alth;2ough normally a Bassics of opiod metabolism: small proportion of oxycodone undergoes CYP2D6 Opioids differs with respect to the means by metabolism to oxymorphone. which they are metabolized, and patients differ in their Tramadol undergoes both CYP3A4- and ability to metabolize individual opioids. However, CYP2D6-mediated metabolism. Methadone is several general patterns of metabolism can be primarily metabolized by CYP3A4 and CYP2B6, discerned. Most opioids undergo extensive first-pass CYP2C8, CYP2D6, CYP2C9 also contributes in metabolism in the liver before entering the systemic varying degree to its metabolism. The complex circulation. First-pass metabolism reduces the interplay of methadone with CYP system, involving as bioavailability of the opioid. Opioids are typically many as 6 different enzymes, is accompanied by lipophilic, which allows them to cross cell membranes considerable interaction potential. (Bathun et al., to reach target tissues. Drug metabolism is ultimately 1999). intended to make a drug hydrophilic to facilitate its The CYP2D6 enzyme is entirely responsible for excretion in the urine. Opioid metabolism takes place the metabolism of hydrocodone, codeine, and primarily in the liver, which produces enzymes for this dihydrocodeine to their active metabolites purpose. (Quang-Cantagrel et al., 2000). (hydromorphone, morphine, and dihydromorphine, These enzymes promote 2 forms of metabolism: respectively), which in turn undergo phase 2 phase 1 metabolism (modification reactions) and glucuronidation. (Mercadante 2000). phase 2 metabolism (conjugation reactions). PHASE 2 metabolism

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Phase 2 metabolism conjugates the drug to CODEINE hydrophilic substances, such as glucuronic acid, Codeine is pro-drug that exerts its analgesic sulfate, glycine, or glutathione. The most important effect after metabolism to morphine. Patients who are phase 2 reaction is glucuronidation, catalyzed by the CYP2D6 poor (offrapid metabolizers) don't respond enzyme uridinediphosphateglucurosyltransferase well to codeine. (Codeine Contin 2007). (UGT). MORPHINE The most important UGT enzyme involved in the Morphine is the gold standard for analgesia and metabolism of opioids that undergo glucuronidation remains the most commonly used opioid because of its (e.g., morphine, hydromorphone, oxymorphone) is relatively low cost and the availability of numerous UGT2B7. Research suggests that UGT2B7-mediated dosage forms. Morphine is metabolized mainly by the opioid metabolism may be altered by interactions with liver and its metabolites are excreted via the kidneys. other drugs that are either substrates or inhibitors of Therefore, it might be excepted that there are this enzyme. Moreover, preliminary data indicate that alteration in morphine disposition in patients with UGT2B7 metabolism of morphine may be potentiated liver disease. (Kotb et al., 2008). by CYP3A4, although the clinical relevance of this Morphine is glucuronidated to 2 metabolites with finding is unknown. (Zhou 2008). potentially important differences in efficacy, The activity of UGT2B7 shows significant clearance, and toxicity: morphine-6-glcuronide (M6G) variability between patients, and several authors have and morphine-3-glucuronide (M3G). Morphine may identified allelic variants of the gene encoding this also undergo minor routes of metabolism, including enzyme. Although the functional importance of these N-demethylation to normorphine or normorphine 6- allelic variants with respect toglucuronidation of glucuronide, diglucuronidation to morphine-3,6- opioids is unknown, at least 2 allelic variants (the diglucuronide, and formation of morphine ethereal UGT2B7-840G and -79 alleles) have been linked to sulfate. substantial reduction of morphine glucuronidation, A recent study found that a small proportion of with resulting accumulation of morphine and morphine is also metabolized to hydromorphone, reduction in metabolite formation. Moreover, research although there are no data suggesting a meaningful has shown that variation in the amount of messenger clinical effect. Like morphine, M6G is a ⌠1-opioid RNA for hepatic nuclear factor 1, a transcription receptor agonist with potent analgesic activity. factor responsible for regulating expression of the Although the affinities of morphine and M6G for the UGT2B7 gene, is associated with interindividual ⌠1-opioid receptor are similar, a study of low dose variation in UGT2B7 enzyme activity. (Zhou 2008). morphine, M6G, and M3G found that morphine had Clinical importance of metabolic pathways: greater analgesic efficacy. The M3G metabolite of Most opioids are metabolized via CYP-mediated morphine lacks analgesic activity, but it exhibits oxidation and have substantial drug interaction neuroexcitatory effects in animals and has been potential. The exceptions are morphine, proposed as a potential cause of such adverse effects hydromorphone, oxymorphone, which undergo as allodynia, myoclonus, and seizures in humans. glucuronidation. In patients prescribed complicated (Coffman et al., 2003). treatment regimens, physicians may consider initiating There is a need to investigate the disposition of treatment with an opioid that is not metabolized by the morphine, in patients with cancer pain as a result of CYP system. However, interactions between opioids primary and secondary liver carcinoma. (Kotb et al., that undergo CYP- mediated metabolism and other 2008). drugs involved with this pathway often can be Patients with liver cancer showed a 3-4 fold addressed by careful dose adjustments, vigilant increase in the peak concentration of morphine therapeutic drug monitoring, and prompt medication presumably as a result of the reduction in first pass changes in the event of serious toxicity (Huber et al., metabolism secondary to a reduction in liver cell 2008). mass; this led to an increase in total systemic PRODUCTION OF ACTIVE METABOLITES bioavailability of morphine. Approximately 70% of Some opioids produce multiple active the dose entered the systemic circulation in patients metabolites after administration. Altered metabolism with liver cancer compared with 20% in healthy due to medical comorbidities, genetic factors, or drug- control. This is reflected in an increase in AUC. drug interactions may disrupt the balance of Systemic clearance was maintained in liver cancer metabolites, thereby altering the efficacy and/or patients with a prolonged elimination half-life in tolerability of the drug. Moreover, opioids that patients with primary liver carcinoma as a result of produce metabolites chemically identical to other cirrhosis. (Kotb et al., 2008). opioid medications may complicate the interpretation Early studies produced conflicting evidence on of urine toxicology screening. the effect of the liver cancer on hepatic drug

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metabolism; limited information is available on norepinephrine reuptake and the more potent promoter hepatic drug metabolism in primary and secondary of serotonin and norepinephrine efflux. (Raritan & liver cancer. Based on the intact hepatocyte theory Ortho-McNeil 2000). Kawasak and co-workers showed that in a group of six Tramadol is centrally acting synthetic opioid patients with liver cancer (three primary and three analgesic commonly prescribed for moderately to metastatic) phenazone clearance was unchanged. severe pain. Its increasing use may relate to the fact (Kotb et al., 2008) that it has less side effects than other opiates, in Clearance of antipyrine was also reported to be particular, less addictive potential less respiratory unchanged by Robertz-Vaupel and colleagues. In depression. (Loughreya et al., 2003). cirrhosis, there is usually marked fibrosis and nodular Tramadol has a dual mode of action; weak regeneration resulting in circulatory changes of binding to m-opiate receptors and reuptake inhibition importance expecting a reduced clearance in patients of serotonin and noradrenalin neurotransmitters. It is with liver cancer on top of cirrhosis. However, there is extensively metabolized by the liver and primarily evidence of increased hepato-arterial flow that is equal excreted in urine. Dose reduction is recommended in or even above that of normal. Vascular changes as a severe renal impairment and liver cirrhosis. The most result of cancer itself may complicate the situation common side effects are dizziness, nausea, further. These mechanisms can in part explain the constipation and headache. We report the first case of maintained clearance of morphine in patients with accidental overdose of tramadol leading to fatal acute liver cancer included in this trial. On the other hand, hepatic failure. (Loughreya et al., 2003). glucuronidation has been shown to be preserved in Tramadol in hepatic patients cirrhosis and even up-regulated. The prolonged half- Tramadol is used in low doses in patients with life in primary liver cancer patients is a result of cirrhosis who are experiencing intractable pain increased volume of distribution as clearance is because of its impact on peripheral pain pathways, maintained in this group of compensated liver partial inhibition of serotonin reuptake, and low patients. Another cause of impaired elimination in affinity for opioid receptors, thought to result in less patients with liver pathology may be the impaired sedation, respiratory depression, and potential for uptake of the drug across the capillarized endothelium tolerance; however, constipation can still be (impaired drug uptake theory). (Kotb et al., 2008). problematic because of anticholinergic adverse There was complete pain control and good effects. Caution should be exercised in administrating patient satisfaction in all liver cancer patients while tramadol to epileptic patients this drug is known to side effects were more frequent in the primary liver lower the seizures threshold. (Kotb et al., 2008). cancer group, especially respiratory depression. In two Morphine, selective serotonin reuptake cases in the study, a high serum morphine inhibitors, tricyclic antidepressants (TCAs), or concentration was noticed in patient above 65 yr of anticonvulsants because it can precipitates serotonin age with normal renal function. Altered blood-brain syndrome. Doses may need to be reduced in patients transport in patients with cirrhotic liver may partly be with renal failure. (Vizcaychipi et al., 2007). responsible for this. (Kotb et al., 2008). Hepatitis and liver failure are listed as possible HYDROMORPHONE adverse effects in some US (Ultram#, Ortho-McNeil) The primary metabolite of hydromorphone, but no UK datasheets for tramadol products. Sixteen hydromorphone-3-glucuronide, has neuro-excitatory individual nonfatal cases of hepatobiliary dysfunction potential similar to or greater than the M3G metabolite associated with tramadol ingestion have been reported of morphine. Hydromorphone is available only in to the Medicines Control Agency. Deaths related to short acting formulations and extended-release tramadol have been reported, both when ingested formulations are recommended in patients with alone in overdose and when taken in combination with chronic pain requiring long-term therapy. (Wright et potentially interacting drugs. However, in these al., 2001). previous reports, death usually followed the ingestion TRAMADOL of large doses and occured within 24 h of ingestion. Like codeine, tramadol requires metabolism to an Blood tramadol concentrations were extremely high active metabolite, O-desmethyltramadol (M1), to be (up to 38 mg/L). In none of the cases were fully effective. Both tramadol and its M1 metabolite biochemical liver dysfunction or post-mortem hepatic exert analgesic effects through opioidergic necrosis noted. (Loughreya et al., 2003) mechanisms (⌠-opioid receptor) and through 2 non- Patients who are apparently ingested more than opioidergic mechanisms, serotonin reuptake inhibition the recommended daily dose of tramadol, although a and norepinephrine reuptake inhibition. Although M1 deliberate overdose was not suspected. Death followed has more potent activity at ⌠-opioid receptor, tramadol the onset of fulminant liver failure, without seizure is the more potent inhibitor of serotonin and activity. The autopsy blood tramadol concentration

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(3.7 mg/L), although well above the therapeutic range, reported, including when pethidine was used for was much lower than previously reported with fatal patient controlled analgesia (PCA). (Mather & Meffin ingestion. It is possible that in these previous cases, 2000). death occured at an early stage dut to cental nervous In Australia alone, between 1975 to 1997, system or respiratory depression before liver injury ADRAC (Adverse Drug Reactions Advisory bocome apparent. We have found no previous cases Committee) received 35 reports describing reports of fatal hepatic failure following tramadol convulsions in association with pethidine, in 17 of ingestion, nor induced any cases of fatal tramadol which pethidine was the only suspected drug. Risk ingestion in a therapeutic seeting. This case factors include repeated dosing of pethidine, with emphasizes the need for careful explanation to patients associated renal insuffiency, Sickle-cell anemia, high of the maximun daily dose and the necessity of doses of pethidine, and the concurrent administration monitoring liver function when prescribing tramadol of phenothiazines or drugs that induce hepatic in a primary care environment. (Loughreya et al., enzymes. (Jiraki 2001). 2003). FENTANYL OXYCODONE Fentanyl is a strong opioid agonist, a Schedule II Oxycodone is metabolized by CYP3A4 to substance. noroxycodone and by CYP2D6 to oxymorphone. Fentanyl is the oldestsynthetic piperidine opioid Noroxycodone is weaker opioid agonist than the agonist, interacting primarily with mu receptors. It is parent compound; but the presence of this active approximately 80 times more potent than morphine metabolite increases the potential for interactions with and is highly lipophilic and binds strongly to plasma other drugs metabolized by the CYP3A4 pathway. proteins. (Pratt & Kaplan 2000). (Stamford & BurduePharma 2007). Fentanyl undergoes extensive metabolism in the PETHIDINE liver. When administered as lozenger for oral Pethidine is metabolized in the liver via 2 transmucosal absorption, a portion is swallowed and is separate pathways, hydrolysis to pethidinic acid subject to first-pass metabolism in the liver and (inactive metabolite) or demethylation by cytochrome possibly small intestine. It is metabolized to P450 to norpethidine, a non opioid active metabolite. hydroxyfentanyl and norfentanyl. (Botta et al., 2003). After 3.6 hours however the elimination half-life of Fentanyl is metabolized by CYP3A4, but to norpethidine is around 14-21 hours with normal renal inactive and nontoxic metabolites. However, CYP3A4 function and 35 hours in renal failure. Norpethidine inhibitors may lead to increased fentanyl blood levels. has half the analgesic potency of pethidine but two to The transdermal formulation has a lag time of 6-12 three times the potency as a central nervous system hours to onset of action after application, and typically (CNS) excitatory agent and may cause anxiety, reaches steady state in 3-6 days. When a patch is hyperreflexia, myoclonus, seizures and mood changes. removed, a subcutaneous reservoir remains, and drug There is not a clear relationship between clearance may take up to 24 hours. (Ferraris et al., neurotoxicity, cumulative does and serum 2002). norpethidine. 6 several cases of seizures have been

Table (3): Metabolic Pathway/Enzyme Involvement Opioid Phase 1 metabolism Phase 2 metabolism Comment Morphine None Glucuronidation via UGT2B7 Codeine CYP2D6 None Hydrocodone CYP2D6 None ;2CYP3D4 Oxycodone None One of the metabolites of hydrocodone is CYP2D6 hydromorphone, which undergoes phase 2 CYP3A4 CYP2B6 glucuronidation. Oxycodone produces a small CYP2C8 amount of oxymorphone, which must undergo Methadone None CYP2C19 subsequent metabolism via glucuronidation. CYP2D6 CYP3A4 and CYP2B6 are the primary enzymes CYP2D9 CYP3A4 involved in methadone metabolism. Other Tramadol CYP2D6 enzymes play a relatively minor role Fentanyl None None Hydromorphone Glucuronidation via UGT2B7 Oxymorphone None Glucuronidation via UGT2B7

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Opioids Without Clinically Relevant Active healthy participants. The ratio of morphine to its Metabolites inactive metabolite M3G was significantly higher in Fentanyl, oxymorphone, and methadone dont cirrhotic patients than in controls. In another study, produce metabolites that are likely to complicate morphine hepatic extraction was compared in 8 treatment. Fentanyl is predominantely converted by healthy participants and 8 patients with cirrhosis. CYP3A4-mediated N-dealkylation to norfentanyl, a (Levine 2003). non-toxic and inactive metabolite; less than 1% is The pharmacokinetics of fentanyl and metabolized to despropiofentanyl, hydroxyfentanyl, methadone, of the frequently used opioids, are not and hydroxynorfentanyl, which also lack clinically significantly affected by hepatic impairment. relevant activity. An active metabolite of Although dose adjustments for these opioids may not oxymorphone, 6-hydroxy-oxymorphone, makes up be required in certain patients with hepatic less than 1% of the administered dose excreted in impairment, clinicians should nonetheless be urine and is metabolized via the same pathway as the extremely cautious when prescribing any opioid for a parent compound, making an imbalance among patient with severe hepatic dysfunction. (Murtagh et metabolites unlikely. al., 2008). Methadone does not produce active metabolites, Pain management in hepatic patient using non- exerting its activity both analgesic and toxic through opioid analgesics: the parent compound. However, methadone has Pain management in patients with cirrhosis is a affinity for N-methyl-D-aspartate receptors; this difficult clinical challenge for health care affinity is thought to account not only for a portion of professionals, and few prospective studies have its analgesic efficacy but also for neurotoxic effects offered an evidence-based approach. In patients with that have been observed with this opioid. (Kreek et al., end stage liver disease, adverse events from analgesics 2003). are frequent, potentially fatal, and often avoidable. HEPATIC IMPAIRMENT Severe complications from analgesia in these patients The liver is the major site of biotransformation include hepatic encepahlopathy, hepatorenal for most opioids. It is therefore not surprising that the syndrome, and gastrointestinal bleeding, which can prescribing information for most frequently prescribed result in substantial morbidity and even death. In opioids recommends caution in patients with hepatic general, acetaminophen at reduced dosing is a safe impairment. option. For example, in patients with moderate to severe In patients with cirrhosis, non-steroidal anti- liver disease, peak plasma levels of oxycodone and its inflammatory drugs should be avoided to avert failure, chief metabolite noroxycodone were increased 50% and opiates should be avoided or used sparingly, with and 20%, respectively, whereas the area under the low and infrequent dosing, to prevent encephalopathy. plasma concentration-time curve for these molecules (Lin & Kim 2008). increased 95% and 65%. Peak plasma concentrations OTCA Medications: of another active metabolites, oxymorphone, were Over-the-counter analgesics, principally decreased by 30% and 40% respectively. Although acetaminophen and NSAIDs, are commonly used oxymorphoneitself does not undergo CYP-mediated medications worldwide. Guidelines for the use of metabolism, a portion of the oxycodone dose is OTCAs in patients with chronic liver disease are not metabolized to oxymorphone by CYP2D6. Failure to readily available despite the possibility that such biotransform oxycodone to oxymorphone may result patients may be more susceptible to adverse reactions. in accumulation of oxycodone and noroxycodone, Patients are often counseled to modify use of these with an associated increase in adverse events. (Foster drugs. Health care professionals frequently 2008). recommend avoidance of use of acetaminophen in The differential effect of hepatic impairment on patients with liver disease or cirrhosis, whereas the metabolism of oxycodone relative to its active NSAIDs are more commonly endorsed. Variability metabolite illustrates the complexities associated with and misconception regarding the safety of OTCAs for opioids that have multiple active metabolites. Hepatic patients with hepatic dysfunction are widespread impairment may also affect metabolism of opioids that among health care professionals. (Rossi et al., 2008). undergo glucuronidation rather than CYP-mediated Nonsteroidal Anti-inflammatory Drugs: metabolism, such as morphine and oxymorphone. In a NSAIDs as a class are largely metabolized by 1990 study, the elimination half-life and peak plasma CYPs, and most are heavily protein bound. As such, concentrations of morphine were significantly altered metabolism and bioavailability that result in increased in 7 patients with severe cirrhosis. The increased serum levels can be anticipated in cirrhotic bioavailability of morphine in these patients was patient. NSAID induced (and idiosyncratic) 101% compared with approximately 47% observed in

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hepatotoxicity has also been well described. (Rossi et Acetaminophen is the most common cause of al., 2008). fulminant hepatic failure in United States, creating the However, in cirrhotic patients with portal perception that it may be dangerous in patients with hypertension, the greater concern with NSAID use is chronic liver disease. (Larson et al., 2005). the associated renal impairment, in particular Moreover, concern is increasing regarding the hepatorenalsyndrome. This is thought to be due to the safety of acetaminophen at a maximal dosage of 4 g/d inhibition of prostaglandins, which leads to a profound in the general population. (US Department of Health decrease in renal perfusion, reduction in GFR, and and Human Services; US Food and Drug marked sodium retention. (Lee 2008). Administration 2010). Cirrhotic patients require prostaglandins to Surveillance data from the United States from counteract the renin-angiotensin-aldosterone and 1990 to 1998 estimated 56.000 emergency department sympathetic systems that reduce perfusion to the visits, 26.000 hospitalizations, and 458 deaths per kidneys. Hepatorenal syndrome is a dreaded and annum because of acetaminophen overdose. (Benson frequently fatal complication of advanced liver et al., 2005). disease. (Laffi et al., 1997). When one considers that 28 billion doses of NSAIDs can cause mucosal bleeding in patients products containing acetaminophen were consmedin at increased risk of bleeding as a result of 2005 alone, the probability of an individual patient thrombocytopenia and coagulopathy associated with without preexisting liver disease or concomitant advanced liver disease. (Castro-Fernandez et al., alcohol consumption developing clinically important 2006). hepatotoxicity or nephrotoxicity when acetaminophen This risk is even greater in patients with portal dosing is limited to less than 4 g/d is exceedingly rare. hypertension-related complications, such as However, liver failure can occur with a 1-time esophageal/gastric varices and portal hypertensive ingestion of high doses of acetaminophen (>12 g in gastropathy or gastric antral vascular ectasias. adults or 250 mg/kg in a child). (Temple et al., 2007). (Castro-Fernandez et al., 2006). Case reports have demonstrated that long-term NSAIDs may be tolerated in patients with mild ingestion (often accidental) of supra-therapeutic doses chronic liver disease, but they should be avoided in all (> 4 g/d) of acetaminophen in patients without known patients with cirrhosis because of the increased risk of liver disease, and therapeutic doses in alcoholic hepatorenal syndrome and the dire consequences patients without cirrhosis, resulted in acute liver relating to this complication. Preventive medicine, failure. (Mofredj et al., 1999). including avoidance of NSAIDs, is exceedingly To address the fact that approximately half of all important in maintaining the clinical stability of cases of acetaminophen-induced acute liver failure are patients with well-compensated cirrhosis. (Castro- due to unintentional overdosing, advisory committees Fernandez et al., 2006). to the Food and Drug Administration (FDA) endorse No prospective studies have assessed the safety relabeling of acetaminophen-containing products to and efficacy of COX-2 inhibitors in the management better inform the consumer of the potential for liver of chronic pain in patients with cirrhosis. Studies injury with supra-therapeutic doses, and while comparing NSAIDs with COX-2 inhibitors in patients concurrently consuming 3 or more alcoholic drinks without underlying liver disease have demonstrated per day. In addition, the advisory committees support similar effectiveness in the treatment of lowering the maximal dosage of acetaminophen to musculoskeletal pain. (Hur et al., 2006). 2600 mg/day and eliminating or reducing the Although some COX-2 inhibitors may protect availability of combination analgesics, most against gastrointestinal bleeding compared with commonly combinations of opioid with NSAIDs, an increased risk of cardiovascular adverse acetaminophen. Opiates can be addictive, and patients events has been observed. Cyclooxygenases are highly may develop tolerance to these agents, necessitating regulated in response to changes in intravascular dose escalation and thereby increasing the risk of volume, and COX-2 is implicated in the mediation of acetaminophen toxicity. (US Department of Health rennin release, sodium regulation, and the and Food Administration 2010). maintenance of renal blood flow. COX-2 inhibitors These recommendations have not been instituted. may reduce portal pressure in cirrhotic patients, but Unfortunately, no prospective, long-term studies have pilot data suggest a decreased GFR in patients with assessed the safety of long-term use of acetaminophen cirrhosis and ascites treated with celecoxib. The safety in patients with cirrhosis. In such patients, the half-life of COX-2 inhibitors needs further study in patients of oral acetaminophen is double that in healthy with cirrhosis. (Guevara et al., 2002). controls, but hepatic injury and renal injury are rare Acetaminophen: when the dosage is limited to less than 4 g/d. This assumption is supported by a double-blind, 2-period

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crossover study of 20 patients with chronic stable liver amitriptyline and doxepin. (Einarsdottir & Bjornsson disease (8 with cirrhosis), who tolerated 2008). acetaminophen at a dosage of 4 g/d for 13 days Anticonvulsants such as carbamazepine or without adverse effects. (Mofredj et al., 1999). gabapentin also have an established role in The prevailing mechanism of acetaminophen- neuropathic pain management. The rationale for their induced hepatotoxicity includes altered metabolism use is that neuropathic pain presumably involves an via CYP activity in combination with depleted imbalance of excitatory and inhibitory glutathione stores that cause accumulation of a neurotransmitters, and anticonvulsants may modulate hepatotoxic intermediate, N-acetyl-pbenzoquinone peripheral and central components of imine (NAPQI). (Bolesta & Haber 2003). neurotransmission to correct this imbalance and thus Studies in patients with cirrhosis have shown that diminish pain. Most anticonvulsants are metabolized CYP activity is not increased and glutathione stores by the liver (via CYPs) and excreted by the renal are not depleted to critical levels in those taking system, once again necessitating lower and less recommended dose of acetaminophen. Glutathione frequent dosing in cirrhotic patients. (Einarsdottir & stores are variable in patients with and without Bjornsson 2008). underlying liver disease but generally have not been Carbamazepine has been reported to cause found to be depleted in cirrhotic patients. On the basis hepatotoxicity in the general population; it may of these data, the longer half-life, and very limited precipitates a rapid deterioration in cirrhotic patients clinical studies, our recommendation (expert opinion) and thus should be avoided. (Harvey 2008). for long-term acetaminophen use (>14 days) in Gabapentin is unique among anticonvulsants cirrhotic patients (not actively drinking alcohol) is for because it is not metabolized by the liver or bound to reducing dosing at 2 to 3 g/d. For short-term use or 1- plasma proteins, making it a preferred anticonvulsant time dosing, 3 to 4 g/d appears safe; however, with the in patients with cirrhosis. However, the general use of new FDA guidelines in mind, a maximum dosage of 2 gabapentin in patients with cirrhosis may be limited to 3 g/d is recommended. (Benson et al., 2005). by other potential adverse effects, including sedation, Other Analgesics: nausea, and dizziness. (Sylvestre 2002). Not infrequently, patient with cirrhosis Doses should be adjusted for renal failure experience neuropathic pain due to neuropathies from because gabapentin is renally excreted. Pregabalin is a variety of causes, including diabetes, alcoholisms, another anticonvulsant shown to be effective for nutrient deficiencies, and cryoglobulinemia. Tricyclic neuropathic pain; its mechanism of action is as a antidepressant such as amitriptyline and imipramine potent ligand for the ˂-2-™ subunit of voltage-gated have been the mainstay treatment of neuropathic pain calcium channels in the central nervous system. for decades, although their use in this capacity is off- (Harvey 2008). label. The exact mechanism of antineuralgic action of Like gabapentin, it is not subject to hepatic these agents is unknown, but they may diminish metabolism and hence may be an appealing agent of chronic pain by blocking presynaptic serotonin and/or choice in cirrhotic patients with neuropathic pain. A noradrenalin reuptake in neurons involved in pain recent case report from Sweden determined that transmission or dampened endogenous opioid pregabalin was a probable cause of acute liver failure systems. Tricyclic antidepressants rely on hepatic in a 61-year-old healthy man with no previous liver biotransformation with first-pass effects (via CYP2D6 disease. (DiMartini et al., 2006). largely) and renal elimination. (Harvey 2008). Although this may have been an idiosyncratic Health care professionals should start a TCA at a event because no further case reports have been low dose because these agents are sedating, and published in literature, clinicians must be mindful of patients may be more susceptible to the increased risk of drug-induced liver injury in patients anticholinergic adverse effects, including dry mouth, with underlying liver disease. (Vizcaychipi et al., blurry vision, drowsiness, tachycardia, and orthostatic 2007). hypotension due to altered metabolism in the setting of liver dysfunction. The clinician and patient must be References particularly watchful for intestinal stasis as an adverse 1. Alan T., Lim., Geraldine Edis, and Henryk Kranz effect of a TCA because this can precipitates hepatic (1983): Postoperative pain control: Conntribution encephalopathy. if TCAs are deemed necessary, of psychological factors and transcutaneous nortriptyline and desipramine are less potent and electrical stimulation; Pain, 1983;17, (2): 179- appear to be less sedating than other TCAs. 188. Additionally, nortriptyline and desipramine may have 2. Almeida T.F., Roizenblatt S, Tufik S. (2004): less tachycardia and hypotension associated with their Afferent pain pathways: A neurochemical use than older and more potent TCAs, particularly review. Brain Res 1000:40.

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