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In addition treatment yellow tongue purchase prometrium 100mg with amex, a significant proportion of perioperative myocardial ischemia is related to reductions in myocardial oxygen supply without hemodynamic aberrations medicine effexor purchase 100mg prometrium fast delivery. Activation of the sympathetic nervous system may trigger coronary vasoconstriction medications zolpidem order cheapest prometrium and prometrium, which may result in myocardial ischemia in patients with atherosclerotic coronary artery disease medications given im buy prometrium 100 mg without prescription. This may occur through direct activation of cardiac sympathetic nerves, as well as through circulating catecholamines, which may contribute to hypercoagulability, a known mediator of adverse outcomes in patients with ischemic heart disease (Burke et al 2011). The efficacy of acupuncture has been more difficult to assess because of the various types of interventions, but a recent review concluded that it reduced opioid consumption and thus was an effective adjuvant for management of postoperative pain (Sun 2008). Cryotherapy is used to decrease swelling and pain following surgery, but its exact mechanism is not known. Cold therapy has the ability to reduce local inflammation by producing local vasoconstriction and decreasing nerve conduction velocity. The use of cryotherapy has controversial data in terms of the efficacy of analgesia. Although tachypnea and hypocapnia are common initially, prolonged increases in the work of breathing may result in 642 Section Four Clinical States/Deep Somatic Tissue meaningful acute postoperative pain independently predicted more intense chronic pain 3 months after surgery (Poleshuck et al 2006). A meta-analysis of seven randomized controlled trials demonstrated a significant reduction in pain scores but no improvement in range of motion or postoperative drainage (Raynor et al 2005). Continuous-flow cold therapy has the capacity to produce local vasoconstriction and may reduce bleeding, edema, and local inflammatory mediators. This practice allows the anesthesiologist to administer a test dose of local anesthetic for evaluation while the patient is still awake. This facilitates the diagnosis of intrathecal, intravascular, or subdural catheter placement and allows confirmation of segmental epidural analgesia when the test dose of local anesthetic is administered. This segmental nature of analgesia mandates the need to place an epidural catheter in a location to cover the dermatomes included in the surgical field. A general guideline for catheter locations in various types of surgeries is as follows: thoracic surgery-upper to lower thoracic; upper abdominal and renal surgery-low thoracic to high lumbar; orthopedic procedures of the lower extremities and lower abdominal and gynecologic surgery-lumbar region. Alternatively, catheter placement should be approximately at the dermatomal level that corresponds to a point intersecting the upper one-third and the lower two-thirds of the surgical incision. The differences among the opioids used for epidural analgesia relate to their duration of action and propensity to produce side effects. Patient factors such as advanced age, small body habitus, morbid obesity, history of sleep apnea, and general debilitation should be considered when initiating epidural analgesia because these conditions are associated with a greater propensity for respiratory complications. Reduced concentrations of opioids should be used when initiating epidural analgesia in such patients. Although epidural analgesia is usually effective, patients may occasionally experience inadequate pain relief. A systematic approach is necessary to evaluate and manage inadequate epidural analgesia. If analgesia remains inadequate, a test dose of a local anesthetic solution, such as 2% lidocaine with 1:200,000 epinephrine, can then be given to evaluate the epidural catheter location. If a bilateral sensory block occurs in a few segmental dermatomes, epidural catheter location is confirmed. In this case the volume of the infusion was probably insufficient for adequate dermatomal coverage, with resultant inadequate analgesia, and increasing the rate of infusion may produce effective analgesia. A unilateral sensory block after administration of a test dose of a local anesthetic is suggestive of the catheter tip residing laterally in or near a neuroforamen. In addition, there may be specific mechanisms that result in the acute postoperative pain condition converting to a persistent pain syndrome (Katz and Seltzer 2009). Presurgical Factors Preoperative pain intensity is a risk factor for persistent postsurgical pain (Katz and Seltzer 2009). For example, the incidence of chronic pain after total knee arthroplasty is increased in osteoarthritis patients who have more pain before surgery (Brander et al 2003). Some preoperative psychosocial factors, such as attitude and mood, appear to be more important than others in promoting surgical recovery (Rosenberger et al 2006). In particular, high catastrophizing has been found to be associated with increased postoperative pain severity and an increased incidence of the development of chronic pain (Khan et al 2011). In fact, in examining factors that contribute to poor pain outcomes at 6 months after total knee arthroplasty, preoperative pain catastrophizing was the only psychological measure that predicted poor outcomes (Riddle et al 2010). Acute Postoperative Factors Intraoperative nerve injury is believed to be a likely causal mechanism in the development of persistent postoperative pain (Katz and Seltzer 2009). This may explain the high incidence of chronic pain after hernia repair or thoracotomy, two procedures that involve cutting or compression of nerves. Surgical trauma induces neuroplastic changes in pain sensitivity such that mechanical hyperalgesia can be demonstrated both in the area of inflammation (primary hyperalgesia) and in the non-inflamed surrounding tissue (secondary hyperalgesia). Many studies have shown that the intensity of acute postoperative pain is a predictive factor for the development of persistent postoperative pain (Kehlet et al 2006). Once bilateral sensory blockade has been documented, adequate analgesia can be maintained with bolus administration of the epidural solution, followed by adjustment of the continuous epidural infusion or patientcontrolled epidural infusion parameters. Finally, lack of sensory blockade after test dose administration indicates that the epidural catheter does not reside in the epidural space. It may also play a vital role in determining the sites of activation for acute postoperative pain (Buvanendran et al 2007). Device safety, in particular, pump programming errors, is always of concern, and newer infusion systems have better software to reduce the incidence of medication errors (Viscusi 2008).

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Currently treatment concussion best buy prometrium, it is appreciated that these descending pathways represent the outflow of a broad array of brain stem and diencephalic structures that can serve to modulate spinal somatic treatment quad tendonitis buy prometrium 100mg without a prescription, motor medications i can take while pregnant order prometrium with amex, and autonomic function by enhancing (see above sections on serotonin) and decreasing spinal afferent excitability medicine zolpidem cheap prometrium 200mg on line. Endogenous Systems Terminals containing norepinephrine and epinephrine are present in the spinal gray and in axons that arise from neurons in the pontine A5, A6 (nucleus locus coeruleus), and A7 (subcoeruleus) cell groups (Westlund et al 1983, Rajaofetra et al 1992). Adrenergic Receptors Adrenaline and noradrenaline act through two major classes of -adrenergic receptors: 1 and 2. Three distinct subtypes of 2adrenergic receptors are distinguished: 2A, 2B, and 2C (see Aantaa et al 1995, Bylund 1995). An 2D receptor was found in the rat and is the rodent homologue of the human 2A receptor (MacKinnon et al 1994). Importantly, these terminals were positive for glutamate transporter type 2 protein. Because this transporter is principally present in interneurons (Todd et al 2003), it was concluded that the 2C protein was present on the terminals of spinal interneurons (Olave and Maxwell 2003). A role for both 1 and 2 subtypes in the dorsal horn in regulating nociceptive transmission appears to be likely. On the other hand, norepinephrine, 396 Section Three Pharmacology and Treatment of Pain As noted above, early work emphasized the probable role of the noradrenergic bulbospinal pathways in regulating spinal function (Anden et al 1966). These effects were reversed by phenoxybenzamine, an adrenergic receptor antagonist (Anden et al 1966). It was demonstrated in the early 1970s that microinjection of -opiate agonists into the brain stem or electrical stimulation of the brain stem suppresses spinal nociceptive reflexes and produces a behaviorally defined analgesia (see Yaksh and Rudy 1978 for early review). Subsequent work demonstrated that supraspinal manipulations that block spinal reflexes or dorsal horn nociceptive neuron firing would (1) evoke the release of noradrenaline from the spinal cord (Hammond et al 1985), (2) be blocked at the spinal level by antagonism of -noradrenergic receptors of the 2 receptor type (Kuraishi et al 1979b, Yaksh 1979, Jensen and Yaksh 1986, Peng et al 1996), and (3) be mimicked by spinal delivery of noradrenaline and other 2-adrenoceptor agonists (Kuraishi et al 1979b, Reddy et al 1980). These findings emphasized the physiological importance of bulbospinal projections and demonstrated the role played by adrenergic systems and the spinal 2 receptor in this control. Dopamine the principal emphasis with regard to catecholamines has been on the role of noradrenergic and adrenergic projections. There is additional support for the potential role of other catecholamines, including dopamine. This amine is present in descending tracts that originate in the A9 and A11 cell groups (Dahlstrom and Fuxe 1964). Activation of this pathway electrically or by iontophoretic delivery of D2 agonists inhibits nociceptive responses in dorsal horn projection neurons. Conversely, these effects were antagonized by D2 receptor antagonists (Fleetwood-Walker et al 1988). Intrathecal delivery of dopamine agonists yielded an antinociceptive action, probably mediated by a D2 action (Jensen and Yaksh 1984, Barasi and Duggal 1985). Serotonin As reviewed above, bulbospinal serotonin projection systems act through a variety of serotonin receptors. It is clear, however, that spinal serotonergic receptors can also display a counter-excitatory (inhibitory) effect. With regard to the 2 receptor subtypes, current work has emphasized the importance of the 2 subtypes in the inhibitory regulation of dorsal horn function. When activated, these 2 receptors lead to a reduction in transmitter release by inhibition of the opening of voltage-sensitive calcium channels and membrane hyperpolarization through an increased K+ current (see North et al 1987, Maze and Tranquilli 1991). Interestingly, it was suggested that 2 inhibition was clearly observed on both A (probably nonpeptidergic) and C fibers. Based on pharmacology, it appears likely that at least some of the presynaptic effects on primary afferents reflect an action characterized by an 2A-subtype pharmacology (Kawasaki et al 2003). This suggests a probable role of this subclass in regulating the polysynaptic drive that leads to augmented dorsal horn output. In the spinal dorsal horn, iontophoretically activated 2 receptors lead to potent and selective inhibition of the nociceptive responses (to heat or pinch) with no effect on innocuous stimuli (FleetwoodWalker et al 1985). Intrathecal delivery of noradrenaline produces potent analgesia in a variety of species, including the rat (Kuraishi 1979a 1979b; Yaksh 1979; Reddy et al 1980; Reddy and Yaksh 1980; Jensen and Yaksh 1986; Peng et al 1996), primate (Yaksh and Reddy 1981), dog (Sabbe et al 1994), and sheep (Waterman et al 1988). Work in humans has provided parallel data showing the potent spinal actions of agents such as clonidine (Eisenach et al 1996). The agonist and antagonist pharmacology of these effects clearly implicates an 2 receptor subtype (Yaksh 1985). In initial work we showed that the antagonist pharmacology of different 2preferring agonists was distinct and proposed the importance of spinal 2C as well as spinal 2A receptors in producing antinociception, with the spinal effects on blood pressure being mediated by the former (Takano et al 1993). However, it now appears likely that only minimal differences exist between agonist-induced analgesic responses in 2A knockout and wild-type mice (Link et al 1996), whereas 2C knockout reveals the particular importance of that receptor subtype to spinal antinociception (Fairbanks et al 2002). Subsequent work has shown similar effects over a broad range of models, including mechanical paw pressure, thermal escape, and the formalin test (Solomon and Gebhart 1988, Bardin et al 1997). Interestingly, after injury there is reduced Cl- export activity in dorsal horn neurons, which leads to accumulation of intracellular Cl- such that activation of the ionophore may now lead to an exit of Cl-. This shift has been suggested to contribute to the hyperpathia that occurs after inflammation and nerve injury (Morales-Aza et al 2011). The glycine ionophore, when activated, increases Cl- conductance in the post-synaptic membrane and reduces the excitability of secondary-order neurons. This excitatory effect is secondary to reduced activity of the membrane Cl- transporter, which changes the reversal potential for Cl- conductance. Under normal conditions, transmembrane [Cl-] is at equilibrium at or just below resting membrane potential.

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The treatment approach can readily supplement other forms of somatic symptoms rectal cancer order 100mg prometrium with mastercard, pharmacological medications 1-z discount 100mg prometrium visa, and psychological treatment symptoms you have diabetes order prometrium amex. They filter information through their pre-existing knowledge and organized representations of knowledge and react accordingly medications covered by medicaid buy prometrium on line amex. Because interaction with the environment is not a static process, attention is directed to the ongoing reciprocal relationships 593 among physical, cognitive, affective, social, and behavioral factors. Cognitive interpretations will also affect how patients portray symptoms to significant others, including health care providers and employers. Overt communication of pain, distress, and suffering will enlist responses that may reinforce pain behavior and impressions about the seriousness, severity, and uncontrollability of the pain. That is, reports of pain may lead physicians to prescribe more potent medications, order additional diagnostic tests, and, in some cases, perform surgery. Family members may express sympathy, excuse the patient from usual responsibilities, and encourage passivity, thereby fostering further physical deconditioning. People with persistent pain often have negative expectations about their own ability and responsibility to exert any control over their pain, and they avoid activities that they believe will exacerbate their pain or contribute to additional pain or injury (Vlaeyen et al 1995). Such negative, maladaptive appraisals about the situation and personal efficacy may reinforce the experience of overreaction to nociceptive stimulation, inactivity, and demoralization. These cognitive appraisals and expectations are postulated to have an effect on behavior and lead to reduced effort, reduced perseverance in the face of difficulty, and activity that may contribute to increased psychological distress (helplessness) and subsequently physical limitations (Gatchel et al 2007). If we accept that pain is a complex, subjective phenomenon that is uniquely experienced by each person, knowledge about idiosyncratic beliefs, appraisals, and coping repertoires becomes critical for optimal treatment planning and for accurately evaluating treatment outcome. Patients proceed at varying paces, and the therapist must be sensitive to individual differences. At times, the therapist may decide not to move to the next phase but will instead address some pressing problems or concerns of the patient that may be interfering with progress. Therapists must realize that flexibility and clinical skills have to be brought to bear throughout the treatment program. Despite the specific techniques used, all cognitive and behavioral treatment approaches are characterized by being presentfocused, active, time-limited, and structured. Therapists are not simply conveyors of information acting on passive patients but serve as educators, coaches, and trainers. They work in concert with the patient (and sometimes family members) to achieve mutually agreed goals (Flor and Turk 2011). A detailed presentation of the comprehensive treatment approach is offered by Turk, Flor, and Williams (Turk and Williams 2009, Flor and Turk 2011). Rather, a variety of resources are available for confronting pain, a pain that will come to be viewed by patients in a more differentiated manner. Although the six phases are listed separately, it is important to appreciate that they overlap. The distinction between phases is designed to highlight the different components of the multidimensional treatment. Moreover, although the treatment as presented follows a logical Phase 1: Assessment the assessment phase serves several distinct functions, as outlined in Box 42-5. Information for assessment is obtained by interviewing patients and significant others, as well as by using standardized self-report measures and observational procedures (Turk and Melzack 2011). During the assessment phase, the psychosocial and behavioral factors that are probably having an impact and the patient responses that might be expected to be important during treatment are evaluated. All this information is integrated with the biomedical data and is used in formulating the components and process of treatment (Turk and Robinson 2011). There should be a close relationship between the information acquired during the initial assessment phase and the nature, focus, and goals of the therapeutic regimen and evaluation of progress.

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Evidence of the in vivo relevance of this centrally mediated form of inflammatory pain sensitization comes from several studies using mice carrying targeted mutations in genes critically involved in these pathways symptoms nausea buy online prometrium. Subsequent work has studied the phenotypes of GlyR3-deficient mice in more detail medicine interactions buy prometrium 200mg online. These studies showed that disruption of the GlyR3 gene did not affect nociceptive responses in the formalin test and after peripheral nerve lesions (Hosl et al 2006) medicine valium purchase cheapest prometrium, which is consistent with the specific involvement of prostaglandins in inflammatory pain symptoms congestive heart failure order 200mg prometrium free shipping. Similar unchanged nociceptive responses were also reported for carrageenan-induced cutaneous inflammation and kaolin/carrageenan-induced arthritis or iodoacetate osteoarthritis (Harvey et al 2009). Intrathecal ketorolac was well tolerated, but its analgesic effects were much less than expected based on preclinical data from animal experiments. It showed some efficacy against sunburn-induced hyperalgesia in volunteers but did not induce significant analgesia against postoperative pain. Diminished Prostaglandin Production As a Source of Other Desired Effects of Cyclooxygenase Inhibitors Diminished formation of prostanoids can also explain most of the anti-inflammatory and antipyretic actions of antipyretic analgesics. Inhibition of platelet aggregation may also be considered a desired effect of antipyretic analgesics. Inhibition of platelet aggregation to a degree relevant for the prevention of arterial thrombosis is primarily seen with low doses of aspirin/acetylsalicylic acid. Increases in spinal endocannabinoid tone might indeed contribute to the spinal analgesic action of indomethacin and flurbiprofen (Guhring et al 2002, Ates et al 2003). A possible contribution of the endocannabinoid system to the analgesic activity of antipyretic analgesics has been studied particularly extensively for acetaminophen/paracetamol. Possible cellular mechanisms of the spinal anti-hyperalgesia include a reduction in the activation of spinal astrocytes (Svensson et al 2007). Schematic representation of the distribution of acidic antipyretic analgesics in the human body (transposition of data from animal experiments to human conditions). Dark areas indicate high concentrations of the acidic antipyretic analgesics: in the stomach and upper gastrointestinal tract wall, blood, liver, bone marrow and spleen (not shown), inflamed tissue. Some acidic antipyretic analgesics are excreted in part unchanged in urine and achieve high concentration in this body fluid; others encounter the enterohepatic circulation and are found in high concentrations as conjugates in bile. Table 32-1 summarizes the most relevant desired and undesired effects of these drugs. The authors have taken all efforts to ensure correct information on drug doses; they do however not take any legal responsibility for incorrect data. Naproxen and several oxicams (meloxicam, piroxicam, and tenoxicam) fall into this group. These compounds owe their slow elimination to slow metabolism together with a high degree of enteropathic circulation. The long half-life (days) does not make these drugs less suitable for the treatment of acute pain of short duration, but their main indication is inflammatory pain likely to persist for days, such as pain in patients with rheumatoid arthritis or bone metastases. Depending on the galenic formulation, fast or slow absorption (and onset of action) may be achieved (Laska et al 1986). Fast absorption is seen, for example, when it is given as a lysin salt (Geisslinger et al 1989). The bioavailability of ibuprofen is close to 100% and elimination is always fast, even in patients suffering from mild or severe impairment of liver or kidney function. Ibuprofen (at low doses) appears to be particularly useful for the treatment of acute occasional inflammatory pain. It may also be used, though with less benefit, for chronic rheumatic diseases (high doses). At high doses the otherwise harmless compound increases in toxicity (Kaufman et al 1993). On the other hand, the R-enantiomer, which accounts for 50% of the usual racemic mixture, is converted to the S-enantiomer in humans (Rudy et al 1991). It is unknown whether use of the pure S-enantiomer offers any benefits (Mayer and Testa 1997). This may cause retarded absorption of the active ingredient because of retention of such monolithic formulations in the stomach for hours or even days. Moreover, diclofenac is subject to considerable first-pass metabolism, which results in limited (about 50%) oral bioavailability. Consequently, lack of therapeutic effect may require adaptation of the dosage or change of the drug. The slightly higher incidence of liver toxicity with diclofenac may result from the high degree of first-pass metabolism, which leads to a host of reactive metabolites (Boelsterli 2003). This group contains other important drugs such as flurbiprofen, indomethacin, lornoxicam, and ketorolac (very potent), as well as ketoprofen and fenoprofen (less active). All show high oral bioavailability and good effectiveness, but also a relatively high risk for unwanted drug effects (Henry et al 1996). Ketorolac is used after surgery in some Aspirin/Acetylsalicylic Acid Aspirin/acetylsalicylic acid deserves special discussion. This selectivity is due to the rapid cleavage of aspirin/acetylsalicylic acid, which leaves little if any intact aspirin/acetylsalicylic acid in the post-hepatic systemic circulation.

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However medicine neurontin buy prometrium 100 mg cheap, there are other receptor families that could be targeted in a similar manner medicine assistance programs prometrium 100 mg visa. For example medications gabapentin proven prometrium 200mg, by targeting intracellular signaling pathways it might be possible to make agents that selectively inhibit processes that sensitize whole families of transducers treatment keratosis pilaris order prometrium in india. Such signaling pathways tend to be complex and multiplexed, however, and questions of specificity to pain need to be addressed. Suppressing Excitability by Membrane Stabilization Many drugs that target Na+ channels are available. Reduced Ca2+ entry at the presynaptic afferent terminal is expected to depress neurotransmission. However, these drugs are also known to suppress subthreshold oscillations and peripheral ectopia (Pan et al 1999; Yang et al 2005, 2009). There is evidence that the membrane-stabilizing action is due to selective activity on the slow component of Na+ conductance (Yang et al 2009), although it remains unclear whether this is a direct effect on Na+ channels or indirect via A2 binding. In each of these cases it is important to know which of the alternative effects is responsible for analgesia. A final example of alternative concepts about the analgesic mechanism of familiar drugs relates to the corticosteroids. Although presumed to provide pain relief by suppressing the immune response, corticosteroids have long been recognized to have a powerful membrane-stabilizing action. They are effective at suppressing neuropathic ectopia (Kingery et al 2001, Seeman 1966, Meyer et al 2011). Moreover, this action is too rapid to be due to suppression of the inflammatory response (Devor et al 1985, Li et al 2011). It is likely that membrane stabilization rather than (or in addition to) anti-inflammatory action is the primary basis for the pain control provided by corticosteroids, especially when administered at high concentration epidurally or by injection into painful trigger points (Travell and Simons 1984). Corticosteroid molecules may reduce ectopia by binding to membrane neurosteroid receptors rather than to classic intracellular corticosteroid receptors. These and other K+ channel openers are currently in development as analgesic drugs. This would allow the use of higher, more effective doses while at the same time making the drugs more tolerable to patients. This, in turn, probably results from their suppression of ectopia by actions other than global suppression of Na+ conductance. Cardiac toxicity is rarely a problem except at unusually high plasma concentrations or in the presence of prior cardiac morbidity. This suggests several ways of reducing the side effects of drugs used in the treatment of neuropathic pain while maintaining efficacy. Selective Targeting One potential approach is to deliver membrane-stabilizing drugs selectively to sites of problematic electrogenesis. For individual patients the key site or sites can in principle be identified by using diagnostic lidocaine blocks. Membrane-stabilizing drugs themselves are sometimes administered spinally (epidurally or intrathecally) to reach relatively high concentrations locally while minimizing systemic spread. Unfortunately, generating channel-selective Na+ channel blockers has proved challenging, and as noted above, observations using knockout and knockdown technologies raise doubt about the promise of this strategy. K+ channel openers are only beginning to be explored in the context of pain control. Global suppression of Na+ conductance, such as with amitriptyline, is a crude tool. Dose-Limiting Adverse Side Effects Overall, most of the systemically administered therapeutic agents with documented clinical efficacy in the relief of neuropathic pain suppress ectopic afferent discharge in injured neurons. With such a variety of different membrane-stabilizing drugs available for clinical use one needs to consider why so few patients with neuropathic pain obtain satisfactory pain relief. Specifically, dose escalation is typically limited by sedation, somnolence, vertigo, and nausea. These side effects are common to all the various membrane-stabilizing drugs that act by suppressing ectopic afferent firing, although not in identical measure. Since the side effects are the same regardless of how these drugs achieve membrane stabilization, one can infer that the common analgesic action of these drugs is closely related to the mechanism whereby they cause sedation and somnolence. Minimizing adverse effects by decoupling analgesia from sedation should be a primary 888 Section Seven Clinical States/Neuropathic Pain or constant. Each diagnosis can be subdivided into types and subtypes and can manifest in varying intensity. Likewise, neuropathic pain conditions are treated with drugs drawn from a variety of families with very different molecular structures: anticonvulsants, antidepressants, local anesthetics, antiarrhythmics, steroids, and opiates. For these reasons it is broadly held that neuropathic pain reflects a spectrum of different conditions with considerable diversity in etiology and neural mechanisms (Attal et al 2008, Treede et al 2008). Even though many events can precipitate painful neuropathy, they all involve a limited set of changes at the structural level (axonopathy and demyelination) and at the functional level (remodeling of specific membrane proteins and enhanced excitability and impulse discharge). Consistently these are the agents that stabilize membrane hyperexcitability and reduce ectopia. Finally, the side effects of the effective drugs tend to be similar (sedation, somnolence, etc. These observations suggest an underlying unity of neural mechanism despite the diversity of clinical diagnoses. The transduction stage of electrogenesis, depolarization of the pacemaker membrane, is a redundant process. Suppress excitability and you have eliminated the ability of all mediators that act on membrane transducer and receptor molecules to generate a pain signal. Likewise, although there are numerous central sensitizing mechanisms, most or perhaps all are dynamically maintained by afferent impulse traffic.

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