Meclizine
Howard Mark Lederman, M.D., Ph.D.
- Director, Immunodeficiency Clinic
- Professor of Pediatrics
https://www.hopkinsmedicine.org/profiles/results/directory/profile/0000112/howard-lederman
This agent is currently in clinical development for the treatment of urinary incontinence (Zatura et al 2010) treatment quincke edema cheap meclizine on line. Bradykinin and its des-Arg metabolite have been implicated in nociceptive processing on the basis of experiments with peptide antagonists of the receptors (B2 and B1) at which they act and, more recently, on the basis of the phenotypes of knockout mice in which either B2 or B1 receptors had been deleted (Ferreira et al 2002, Mason et al 2002) symptoms valley fever best purchase meclizine. Studies on these knockout mice have also led to the conclusion that these kinins have an important spinal role in the nociceptive process (Ferreira et al 2002) treatment xyy order meclizine 25mg on line. In addition, it has been shown that nerve injury in the mouse (Rashid et al 2004) or the production of paw inflammation in the rabbit (Mason et al 2002) reveals a dominant role for the B1 receptor in nociception, which has led to the suggestion that B1 antagonists might be clinically useful analgesics with efficacy similar to that of the opioids symptoms at 4 weeks pregnant purchase genuine meclizine online. In the rabbit the B1 peptide antagonist B9858 will attenuate a nociceptive spinal reflex when paw inflammation is present but has little effect in the absence of inflammatory sensitization (Mason et al 2002) harrison internal medicine generic meclizine 25 mg with amex. Lanepitant also had no effect on pain in patients with moderate to severe osteoarthritis (Goldstein et al 1998) treatment algorithm meclizine 25 mg online. L-758,298, an intravenous prodrug of aprepitant, failed to abort migraine pain as measured either by the time to meaningful relief or by the number of patients reporting pain relief within 4 hours (Boyce and Hill 2004). Furthermore, prophylactic administration of lanepitant (200 mg/day orally) for 1 month had no effect on migraine frequency and severity when compared with placebo (Goldstein et al 1999). Only a small number of these peptides have been studied to the point of examining compounds interacting with their specific receptors or release mechanisms, and even fewer have advanced to preclinical or clinical development. In particular, there is persuasive clinical evidence that this peptide has a causative function in migraine headache (Edvinsson 2003). Its efficacy was similar to that of the triptans, and no serious adverse effects occurred in this 126-patient study. This approach has expanded recently with the use of membrane-stabilizing anticonvulsant drugs to treat various intractable pain conditions. The molecular biology of ion channels is now sufficiently well understood to allow the rational design of blockers for a single channel subtype. Many established drugs, such as morphine, exert their effects by influencing the activity of ion channels indirectly by activating receptors that are coupled to ion channels via secondmessenger systems. This section is not concerned with such drugs but rather with those that directly influence the activity of voltage-gated ion channels. Reviews of this area can be found in articles by Kaczorowski and colleagues (2008) and Cregg and colleagues (2010). Sodium Channels Na channels are overexpressed in biopsy specimens taken from painful neuromas (England et al 1996). Cloning and expression of the channels (Akopian et al 1996) make this an achievable objective. There is much room for improvement; for example, lidocaine (lignocaine) does not select between Na channels in neurons and those in other tissues, and in molar terms it is a rather weak blocker. Its use-dependent mechanism of action has allowed safe application as a local anesthetic (Murdoch Ritchie 1994), and this is likely to be an important property of any novel Na channel blockers. When given intravenously, lidocaine (lignocaine) has been found to be effective in the treatment of a number of neuropathic pain states, whereas efficacy against other types of pain is the subject of debate, with positive and negative studies being reported. If the infusion rate is limited to 5 mg/kg/hr (Field at al 1997), side effects are mild with minimal cardiovascular changes. Pain relief after a 1-hour infusion lasts several hours and on occasion very much longer. It has also been found to be effective against migraine headache when given intranasally (Maizels et al 1996). Patches containing 5% lidocaine (lignocaine) have been found to be effective and safe in treating the pain of post-herpetic neuralgia and are now being evaluated for the treatment of other pain conditions (Dworkin et al 2007). In particular, a study involving patients with diabetic neuropathy indicated significant improvement in pain and quality of life (Barbano et al 2004). Lamotrigine may prove useful in the treatment of neuropathic pain in patients infected with human immunodeficiency virus (Simpson et al 2003), and the recent demonstration that it reduces cold-induced pain in volunteer subjects may indicate wider utility in treating other types of pain (Webb and Kamali 1998). The more recently introduced anticonvulsant topiramate has shown efficacy in animal experiments, which suggests that it should be useful against neuropathic pain (Tremont-Lukats et al 2000), and some clinical reports suggest that it may be effective against trigeminal neuralgia. This orally bioavailable compound is well tolerated with no signs of neurological or cardiovascular effects at antinociceptive doses. It is also relevant to note that tricyclic antidepressants have been shown to block neuronal Na channels, and this may account for some of the analgesic activity of this class of compounds (Pancrazio et al 1998). Calcium Channels the neuronal voltage-gated Ca channels are a large and complex family with L-, N-, P-, Q-, R-, and T-type currents found in brain and other neuronal tissues. This diversity, though potentially confusing, provides a number of alternative targets for the design of new analgesic drugs. Blockers of L-type Ca currents are the most accessible since they have been used to treat cardiovascular disorders for many years. Although cardiovascular effects may limit their utility, it has recently been shown that nimodipine will reduce the daily dose of morphine needed to provide pain relief in a group of cancer 560 Section Three Pharmacology and Treatment of Pain anticonvulsants and tricyclics (Tremont-Lukats et al 2000, Rice et al 2001). Gabapentin has been found to enhance the analgesic effects of morphine in healthy volunteers (Eckhardt et al 2000) and has been used successfully as part of a post-surgical analgesic regimen after breast cancer surgery (Fassoulaki et al 2002) and after total abdominal hysterectomy (Turan et al 2004). The mode of action of this drug is at least in part due to blocking the action of presynaptic Ca channels since it binds with high affinity to the 2 calcium channel subunit (Gee et al 1996). A more potent analogue (pregabalin, S-(+)-3-isobutylgaba) has also been introduced and has now been registered in both the United States and the United Kingdom for the treatment of neuropathic pain and fibromyalgia (Dworkin et al 2007). This approval was based on studies in patients with post-herpetic neuralgia and diabetic neuropathy in which it was demonstrated that 47% of the patients had a 50% reduction in pain. The main dose-related side effects were dizziness and somnolence of mild to moderate intensity. It has been shown to be effective in a randomized doubleblind study in patients with postoperative dental pain (Hill et al 2001) and, in a variety of animal tests, has a profile similar to that of gabapentin (Bryans and Wustrow 1999). Recent studies have shown it to be effective in treating the pain of post-herpetic neuralgia and, in particular, to improve sleep and mood disturbance (Dworkin et al 2007). Epidural verapamil has been shown to reduce analgesic consumption in patients after lower abdominal surgery (Choe et al 1998). N-, P-, and Q-type Ca currents have all been implicated in pain perception on the basis of anatomical location and animal experiments with invertebrate toxins that show some specificity for the individual channels. Because these toxins are peptides, it is necessary to apply them intrathecally (Malmberg and Yaksh 1995), but they produce striking effects at extremely low doses in a variety of tests, including the formalin and hot plate tests, and continuous infusion for 7 days results in maintained elevation of the nociceptive threshold. Spinal cord neuronal recordings in the presence and absence of inflammatory stimuli suggest that the N channel may be important in the development of spinal cord hyperexcitability and hyperalgesia (Neugebauer et al 1996, Nebe et al 1998). Well-controlled, intrathecal studies of ziconotide in humans have indicated that it produces pain relief in patients with severe refractory pain secondary to cancer or acquired immunodeficiency syndrome (Staats et al 2004). It is now approved for clinical use in the United States and the European Union for patients with severe pain refractory to other treatments (Schmitko et al 2010). Other related cone snail toxins are also in development for the treatment of pain, but no clinical data are yet available (Nelson 2004). Considerable progress has been made in the synthesis of selective, small-molecule N-type channel blockers (Zamponi et al 2009, Abbadie et al 2010), although initial attempts to show clinical efficacy in relieving pain have been unsuccessful. Peptide blockers of P-type channels have also been studied for their antinociceptive effects in animals. They appear to be most effective in the presence of inflammation (Nebe et al 1997) and have a different effect from N-type channel blockers in that they attenuate the late but not the early phase of the formalin response (Diaz and Dickenson 1997). No information is yet available about the action of P-type channel blockers in humans, but it is important to note that mutation of P/Q-type calcium channels has been associated with the occurrence of familial hemiplegic migraine (Ophoff et al 1996), thus suggesting one logical therapeutic use for blockers of this channel, although the phenotype of knockout mice suggests that blockers of this channel may not be usable without serious side effects or even lethality. Gabapentin is a chemically novel anticonvulsant agent that is proving useful for the treatment of neuropathic pain (Rosner et al 1996, Rosenberg et al 1997, Backonja and Glanzman 2003), especially post-herpetic neuralgia (Rice et al 2001, Scheinfeld 2003). Recent detailed knowledge of the molecular biology of cholinoceptors has made it possible to design agents that are receptor subtype selective and thus may have an improved ratio of wanted to unwanted effects. The cholinergic analgesia story was revived following the discovery (Spande et al 1992) that epibatidine, an alkaloid extracted from the skin of an Ecuadorian frog, was a more potent analgesic than morphine. This compound was subsequently shown to be a potent nicotinic agonist (Badio and Daley 1994) but was too toxic to be developed as a clinical analgesic (Rupniak et al 1994). It has moderate affinity at autonomic and sensory ganglion (3-containing) receptors (Donelly-Roberts et al 1998). Acute dosing caused a decrease in locomotor activity, a decrease in body temperature, and loss of balance, but these effects, unlike the antinociception, showed tolerance on repeated dosing. Such administration produced initial nociceptive behavior, consistent with the pain seen when capsaicin is injected or applied topically in humans, followed by prolonged elevation of nociceptive thresholds. Preparations containing capsaicin for topical application are now widely available and are sometimes effective in relieving painful conditions involving unmyelinated fiber dysfunction. Such conditions include post-herpetic neuralgia, post-mastectomy pain, and diabetic neuropathy (Szallasi 1997). A systematic review of the use of topical capsaicin for pain concluded that it had only moderate or poor efficacy and was likely to be most useful in patients intolerant of other treatments (Mason et al 2004). Commercial preparations generally contain only low concentrations of capsaicin (<1%), and even at this dose compliance can be low because of the burning sensation experienced on application. Marked temporary pain relief was obtained in 9 of 10 patients, with 7 of them achieving significant and prolonged pain relief on repeated application. A transient increase in pain can be seen before the pain-relieving effect becomes apparent, but the side effects are manageable (Backonja et al 2008, Horsley 2011). Capsaicin is not suitable for oral administration in humans because it is poorly absorbed from and highly irritant to the gastrointestinal tract. It is not yet clear whether it is necessary to first stimulate the receptor to desensitize it (causing the patient discomfort) or whether it might be possible to block the receptor painlessly with a silent antagonist or partial agonist and yet still provide clinical pain relief. Workers at Novartis have produced analogues of capsaicin that are not pain producing yet still have antinociceptive properties in animals and are free of unwanted bronchoconstrictor activity. One of these drugs entered clinical development as a potential analgesic (Wrigglesworth et al 1996). A number of novel mechanisms are being studied through compounds currently in clinical trials, and other novel approaches are in preclinical development. A rich source of new drugs for treating pain continues to be the empirical observation of beneficial properties of drugs introduced for the treatment of other conditions, especially anticonvulsants. The latest in a long line of such drugs is levetiracetam, which was initially found to be useful in three cases of neuropathic pain (Price 2004) and has now been studied for neuropathy, radiculopathy, and headache, where addition to normal pain medication regimens was found to improve both pain and anxiety in about 80% of a group of 53 patients (Kaplan and Kaplan 2004). Our approach to all new hypotheses needs to be cautious until we have solid clinical evidence of efficacy and safety from randomized, double-blind, placebo-controlled trials. The recent failure of agents in clinical evaluation and the limited novelty of the approach taken in the recent past (Kissin 2010) underline the fact that there is still an urgent need for original basic research to underpin the discovery of further novel analgesics. In Villaneuva L, Dickenson A, Ollat H, editors: the pain system in normal and pathological states: a primer for clinicians.
Finally, there is evidence that anxiety (panic disorder, generalized anxiety disorder) has an even stronger association with pain than depression does (McWilliams et al 2004) medicine search purchase genuine meclizine line. Addiction is a chronic neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations medications peripheral neuropathy buy discount meclizine. It is characterized by impaired control over use, compulsive use, craving, and continued use despite physical, psychological, or social harm treatment uterine fibroids buy meclizine overnight. The diagnosis of addiction can be made only prospectively over time while observing for a pattern of compulsive and impaired control over medication use, craving in the absence of outof-control pain, and use despite harm silent treatment order meclizine 25 mg with mastercard. Most important, such behavior does not resolve easily when other possible causes of the behavior are appropriately addressed xanax medications for anxiety buy meclizine 25mg with mastercard. A much more relevant issue, however, is the incidence of de novo addiction on opioid exposure medicine ketorolac effective 25 mg meclizine. For studies that preselected patients for no addiction history, the incidence of addiction decreased to 0. Some recent studies (Boscarino et al 2010) not included in this review have indicated that the prevalence of current opioid dependence may be as high as 26%. Here, the diagnosis revolved around two problematic criteria: the pain was inconsistent with its anatomic distribution, lacked organic pathology accounting for it, or was grossly in excess of that expected from the physical findings, and psychological factors had to be etiologically related to the development of pain. Therefore, the psychiatric examiner had to make a difficult judgment and then, in addition, had to judge the importance of psychological factors. In another study, Fishbain and colleagues (1998) in a meta-analytic review of antidepressant treatment of pain in patients with somatoform pain disorder and psychogenic pain disorder reported that antidepressants were effective for the pain of somatoform pain disorder. This diagnosis now contains three criteria: (1) the pain must involve one or more anatomical sites and be the predominate focus of the clinical findings; (2) the pain must cause clinically significant distress and impairment in social, occupational, or other important areas of function; and (3) psychological factors must play an important role in the onset, severity, exacerbation, and maintenance of pain. These criteria should then also be of little diagnostic validity and should be overinclusive. This may be related to more severe disc degeneration in smokers as a result of increased serum proteolytic activity caused by nicotine, which speeds up disc degeneration. Smokers have a higher prevalence of musculoskeletal disorders than do non-smokers reporting greater pain. Interestingly, nicotine has an antinociceptive (analgesic) effect, which could be the motivation for smoking behavior. In psychiatric patients, smoking is associated with alcoholism, illicit drug use, depression, panic disorder, severe mental illness, cognitive decline, suicide attempts, suicidal thoughts, suicide completions, and decreased probability of recovery from suicidal ideation. The association of depression/suicide with smoking may be related to impairment of serotonin function by nicotine. Such a finding casts doubts on the behavioral theory behind psychogenic pain/somatoform pain disorder/pain disorder. Accordingly, this diagnosis should be used with extreme caution until further research is available. Typically, pain does not allow them to go to sleep, and when they do go to sleep, the pain wakes them up. This raises the question of whether the sleep problem is etiologically related to the pain. A number of reviewers have concluded that there is an association between chronic pain and sleep problems. Studies addressing primary sleep disorders, sleep disorder related to a mental disorder, and substanceinduced sleep disorders were excluded. The remaining studies were subdivided by the type of analysis performed (prospective, path analysis, correlation, univariate, do non-sedating drugs that improve pain improve sleep). In all these groups, 100% of the studies supported the hypothesis of an etiological relationship between pain and sleep (pain causing the sleep disorder). However, a number of studies have demonstrated that sleep restriction in healthy pain-free normal sleepers will cause hyperalgesia on pain stimulation after sleep restriction. Second, nocturnal sleep disturbance is a predictor of suicide attempts in psychiatric outpatients. The two criteria for this disorder are the presence of the symptom and judgment by the psychiatric examiner that psychological factors are associated with initiation (preceded by conflict or other stressors) or exacerbation of the symptom. In rodent models of mononeuropathy, stocking or glove hypoesthesia is the result of extraterritorial sensory loss secondary to overlapping receptive fields of adjacent neurons in the spinal cord. Motor conversion is almost always associated with the presence of pain in the affected extremity. Muscle pain reduces maximal voluntary contraction and endurance time during submaximal contractions. In pain induction studies, motor unit firing rates are inversely related to reports of pain in rapidly activated painful and pain-free synergistic muscle. Overall, this research indicates that the neurophysiological phenomena of pain are intimately involved in the generation of these two "conversion" symptoms and are not caused by behavioral issues as the diagnosis implies. Typically, the individual complains of no desire for sex because sex hurts or that since onset of the pain, interest in sex has decreased. In a recent fibromyalgia study, the female sexual function index was shown to negatively correlate with pain score and with the presence of sexual dysfunction in fibromyalgia patients as compared with controls. In one prospective study measuring the effect of intrathecal opioid therapy on serum testosterone levels, serum testosterone was reduced by 74% after week 1 (Cole 2007). These cognitive complaints are secondary to pain interfering with focusing of attention. Pain level inversely correlates with neuropsychological testing performance (Weiner et al 2006). In addition, some evidence indicates that opioids may under some circumstances interfere with cognitive function. This type of cognitive dysfunction is similar to that found with mild cognitive impairment (Watson et al 2009), which is usually classified under cognitive disorder, not otherwise specified. Also, in studies of depressed primary care patients, pain appears to be a significant predictor of suicidal ideation. Passive suicidal ideation is associated with a family history of suicidality, sleep-onset insomnia, abdominal pain, high pain intensity, and neuropathic pain (decreased risk). Active suicidal ideation is associated with a family history of suicide attempts or completions. In a cohort of community residents who were documented through court records to have been abused in early childhood, pain symptoms in young adulthood were associated with known victimization status. In the last prospective study, a history of abuse did not predict the development of chronic widespread pain in patients in whom regional back and/or neck pain had developed. Raphael and associates (2004) listed the deficits of this literature: (1) studies did not isolate the effect of childhood abuse from adult abuse; (2) studies combined childhood sexual abuse with childhood physical abuse; (3) studies recruited subjects from tertiary clinical settings, which is problematic because there is a relationship between health care seeking and self-reported abuse status; (4) studies did not control for psychiatric disorders, which can increase treatment seeking and inflate the incidence of abuse; (5) studies did not control for gender composition, which can confound group comparisons because men and women may experience different types of abuse; (6) studies used interview techniques, which are less likely than anonymous questionnaires to generate report of abuse; (7) the small sample size of studies led to problems of being underpowered to discern a modest relationship; (8) studies were crosssectional and used non-consecutive or non-random samples; (9) studies used control populations that did not represent the universe of the population under study; and (10) it is difficult to interpret the results of abuse studies because the prevalence is not known in a comparable general population. Overall, the results of these reviews and prospective studies indicate that the relationship between childhood abuse and pain in adulthood, if present, may be weak, with large sample sizes being required to demonstrate a small relationship. A meta-analysis demonstrated a relationship between sexual abuse and the presence of some somatic disorders (functional gastrointestinal disorders, non-specific chronic pain, psychogenic seizures, chronic pelvic pain) but not others (fibromyalgia, obesity, headache) (Paras et al 2009). Overall, this literature indicates that childhood sexual abuse could be an important variable in the etiology of chronic pain and should be investigated further. Death by suicide has been shown to be associated with the presence of depression and increased pain. Recently, a study (Fishbain et al 2010a) using community patients as a control group demonstrated the following: (1) chronic anger was affirmed by 8. Significant research also indicates that anger may be important in pain perception: (1) elevations in pain increase the tendency for anger-out, (2) efforts to suppress anger may increase pain, (3) expressing anger may improve pain control, and (4) swearing in response to pain may increase tolerance of the pain. This could be a function of a physiological or behavioral response to control pain in individuals predisposed to anger. Studies addressing this issue have generated inconsistent findings, which has resulted in conflicting reviews (Raphael et al 2004). A structured evidence-based review of 23 reports concluded that there is an association between pain and fatigue and that the relationship may be etiological (Fishbain 2003a). In this study, 697 patients with diabetic neuropathic pain were treated with 20 mg of duloxetine, and changes in vitality with the drug were shown to be superior to placebo. In addition, path analysis indicated that improvement in vitality was secondary to improvement in pain (Fishbain et al 2009). A recent study on the longitudinal association between pain and fatigue demonstrated that pain and fatigue are directly associated in time (Nijroldeir et al 2010). Overall, this literature indicates that clinicians should inquire about fatigue and initiate treatment to improve fatigue. Being obese is associated with increased risk for fibromyalgia, and fibromyalgia body mass index predicts restriction of pain-related function. Obese fibromyalgia patients have significantly greater pain sensitivity to tender point palpation than do non-obese fibromyalgia patients. Consequently, clinicians should target this co-morbidity and avoid making it worse if possible by not prescribing medications that could increase weight. Secondary gain was defined by Freud as interpersonal or social advantage attained by the patient as a consequence of illness, with it being unconsciously motivated. This definition was used by others to define some specific alleged gains as a consequence of illness, such as loss of a hazardous work condition, sympathy from family, ability to withdraw from an unpleasant life role, financial rewards associated with disability, and others. Although there are numerous potential secondary gains, the term has become synonymous with financial rewards associated with disability. Accordingly, the presence of litigation or disability benefits leads to the accusation of potential secondary gain, which is then equated with malingering (Fishbain 1994). Secondary gain can occur by unconscious mechanisms, whereas malingering is conscious. Frequently, the secondary losses incurred by taking on the sick role far outweigh financial and other gains. In reference to litigation and having a lawyer, some authors have claimed that litigation promotes attitudinal distortions and conscious and unconscious motivation for secondary gain. There is significant evidence (Greenough and Fraser 1989) that the presence of litigation or a lawyer delays recovery from injury. Some authors have also suggested that litigation may function as a coping response. It is a predictor of longer claims, and as the ratio of compensation to preinjury wage increases, the duration of the claim increases (Teasell 2001). In Saskatchewan, Canada, the tort compensation system for traffic injuries was 280 Section Two Assessment and Psychology of Pain symptoms that are not fully explainable. It is important to keep in mind that the problem of unexplained medical symptoms may be a function of the limitations of our diagnostic acumen and technology. For example, until recently, fibromyalgia was considered to be an unexplained symptom problem, whereas we now know that fibromyalgia may be a central pain hypersensitivity problem. There are also other forms of malingering: malingered omission (conscious withholding of information despite direct inquiry), partial malingering (conscious exaggeration of symptoms that do exist), false imputation (ascribing actual symptoms to a cause consciously recognized not to be related), and dissimulation (concealment or minimization of symptoms). Some of these types of malingering were demonstrated in the studies covered under the secondary gain descriptions (see earlier). This study also concluded that malingering cannot be reliably identified by facial expression, questionnaire, sensory testing, clinical examination, Jamar dynamometer, and isokinetic testing (Fishbain 1999). It is unclear whether secondary gain and compensation status translate into actual malingering and into what type. These signs then became very popular, with clinicians performing independent medical examinations for insurers in chronic pain litigation to raise the specter of malingering or conversion. There is rodent evidence of painful peripheral neuropathies causing non-dermatomal extraterritorial pain, and in humans, areas of pain-related hypoesthesia can be reduced or removed by relieving pain. Meta-analytic integration of 244 studies has found that four somatic syndromes (irritable bowel, non-ulcer dyspepsia, fibromyalgia, chronic fatigue syndrome) are related to but are not fully dependent on anxiety and depression. This does not mean that anxiety and depression symptoms are the cause of the unexplained symptoms since they could be a reaction to the unexplained symptom, but nevertheless, the mood symptoms are often unrecognized (Aguera et al 2010). If this is the case, the physician should then undertake to diffuse this perception. There is also some recent evidence that most of the tender point sites in fibromyalgia are actually myofascial trigger points. In an evidence-based structured review of 57 studies, somatization as measured by inventories was shown to be consistently associated with the presence of chronic pain, and somatization correlated with pain intensity. Another review demonstrated that somatization studies rarely investigated whether the symptoms were unaccounted for by pathological findings, thereby not fulfilling the aforementioned definition (Crombez et al 2009). Fibromyalgia may be a neuropathic pain condition rather than a soft tissue syndrome (Fishbain et al 2008). In addition, some of this somatic co-morbidity may be pain determined in that improving the pain may improve the somatic co-morbidity. Finally, this literature also indicates that somatic symptoms cluster together and that these clusters differ between pain severity groups. Although this has not been investigated, it is likely that these clusters will respond to psychopharmacological treatment as a cluster of somatic symptoms (together). Recently, there has been significant research on the relationship between pain and somatic symptoms other than pain. This research is as follows: first, the total number of somatic symptoms increases the risk for significant chronic disabling pain. Second, there appears to be a reciprocal relationship between somatic symptoms other than pain and pain in that decreases in pain are associated with a decreased number of somatic symptoms. Sixth, patients with somatic symptoms and depression respond less well to pharmacological treatment of depression, possibly because improvement in somatic symptoms typically plateaus, which is different from the depression response.
Buy discount meclizine on line. The Girl Who Couldn't Wake Up: Hypopituitarism | Medical Documentary | Reel Truth.
Obviously, to learn a new habit such as riding a bike or tying shoelaces, one needs to initially be aware of movement and the results of different motor strategies medications with sulfa purchase meclizine australia. With time, however, this conscious process becomes automatic and unconscious and therefore somewhat independent of the final goal symptoms 7dpiui generic 25mg meclizine visa. It is thought that the dorsal striatum plays an important role in habit formation, usually under the control of the prefrontal cortex-the "executive control" system (Robbins and Everitt 2002, Berke 2003) treatment lupus cheap meclizine online. It is the failure of cortical executive control together with a strong habit formation that has been postulated to account for many aspects of addiction and relapse medicine rash purchase meclizine 25mg without a prescription. There is some evidence that a limited number of these changes may contribute to sensitization, tolerance, and withdrawal, but establishment of the addicted state has yet to find molecular correlates medicine 968 generic 25 mg meclizine amex. In any case, the idea that within this battery of genes are a small number that directly cause the shift from drug taking to addiction has been criticized medicine 801 discount 25 mg meclizine with mastercard. Several components of the pathway have been shown to change activity, including adenylyl cyclase. Activation of D1 results in stimulation of adenylyl cyclase, whereas D2 receptor stimulation inhibits cyclase activity. Changes in protein synthesis would in any case occur too slowly to support the behavior. The development of drug self-administration behavior is slow by comparison: rats tend to press levers compulsively for heroin self-administration after one or two successful pairings of bar pressing and intravenous heroin injection but then tend to respond at a rate of two or three bar presses per hour. Nevertheless, some aspects of drug taking have been replicated by the manipulation of specific brain pathways. However, from studies of antagonists and in mice with each receptor gene selectively deleted via homologous recombination, the receptor has been shown to mediate most of the analgesic and rewarding effects of the drug. In the striatum these pathways appear to be mutually inhibitory at many stages, but their effects inside the nucleus can be cooperative. Some genes appear to be part of a homeostatic response whereby sensitivity to subsequent stimulation is reduced; others may be involved in consolidating changes in the strength of specific synaptic connections. However, it may well be that many of the changes in gene expression are part of a homeostatic attempt to drive down or increase levels of synaptic activity back to normal pre-drug levels and do not predispose the system to compulsive drug seeking (Wise 2002). Opiate withdrawal symptoms develop primarily as a result of intense activation of the central noradrenergic and serotonergic pathways, as well as from dopaminergic function following cessation of chronic drug treatment. Standard therapeutic strategies for managing withdrawal symptoms in heroin addicts include treatment with noradrenergic 2 receptor agonists, which in part inhibit release of noradrenaline (norepinephrine). These animals also showed behavioral sensitization to the administered drug (Hyman and Malenka 2001, Saal et al 2003). Overexpression of the FosB gene in the nucleus accumbens of mice enhances the rewarding effects of morphine, thus pointing to a role of this transcription factor in the molecular events that underlie sensitization. Opiates acutely inhibit locus coeruleus neurons by increasing the conductance of an inwardly rectifying K+ channel through coupling with subtypes of Gi/o, as well as by decreasing an Na+-dependent inward current through coupling with Gi/o and consequent inhibition of adenylyl cyclase. Upward bold arrows summarize the effects of chronic morphine administration in the locus coeruleus. It has also been argued that an unconscious habit succeeds because the cortical decision is aberrant rather than that the strength of the habit is overwhelming. In this light, rehabilitation from drug addiction can be seen very much as realignment of decision making and encouragement of the selection of more appropriate choices. Evoking learning and memory processes in the transition between drug taking and compulsive drug use also has resonance with other aspects of the response to opiate treatment. For example, the development of opiate tolerance and sensitization can be associated with the environmental context. It was shown (Mitchell et al 2000) that the development of opiate tolerance in rats could be related to environmental cues and that this process was modulated by release of the neuropeptide cholecystokinin within the amygdala. Similarly, locomotor sensitization to opiate drugs is susceptible to environmental associations. In rats, increased locomotion in response to repeated drug administration can be eliminated by changing the test environment from the place in which repeated drug injections had been previously given (Berke and Hyman 2000). In the addicted state the relationships between loss of homeostatic control, increased incentive salience of the drug, and the newly formed drug habit are still unclear, but involvement of the mesolimbic system and the dorsal parts of the corpus striatum may well be crucial. Of particular interest was the observation that stress itself was enough to trigger sensitization. A considerable amount of research supports the familiar observation that stress can reinstate drug taking. Similarly, suppression of stress-induced corticosterone secretion abolishes the enhanced behavioral response to opiates produced by different stressors. Learning and Memory Finally, we have to consider whether any of these molecular changes contribute to the transition from drug taking to the addictive state characterized by compulsion and craving for a drug. There is a growing body of evidence that aberrant learning and memory mechanisms may be at fault and that addiction is in fact nothing more than a very strong habit triggered by cues associated with drug taking, such as the paraphernalia associated with drug taking or the street or bar where the drug was obtained. It has been argued that the standard definition of compulsion as "an inner drive that causes a person to perform actions, often of a trivial and repetitive nature, against their will" (Collins Dictionary) is inappropriate when applied to drug addiction. It has also been argued (Berke 2003) that although there may be excessive "wanting" (increased incentive salience) of the drug, the compulsion to take drugs and relapse into drug taking results from the lack of frontal cortical executive control over a very strong habit laid down in subcortical regions of the brain. There is growing evidence that the striatum may be involved in habit formation (White 1997, Jog et al 1999, Saka et al 2002) and uses many of the synaptic mechanisms generally used to describe the establishment of learning and memory. This would account for the altered synaptic physiology and long-term remodeling of dendritic morphology that have been found following chronic drug treatment (Robinson and Kolb 2004). In this formulation, which relies heavily on habit formation, craving-"to desire intensely"-is not a continuous process but one triggered by cues associated with previous drug experience and not present when such environmental contingencies are absent. Berke (2003) concluded that "addiction can be seen as an extension or exaggeration of our normal human difficulties with controlling our behavior to conform with long-term personal or societal goals. Until relatively recently there were no good animal models that distinguished simple drug administration from the compulsive drug taking that characterizes addiction. However, recent research has shown that when rats self-administer cocaine over an extended period, their motivation increases and intake of drug escalates. A small proportion of rats (17%) also showed another key feature of addiction, continued drug use in the face of adverse conditions-in this case, electric shock and continued drug seeking when drug has been removed. Remarkably, the proportion of rats that eventually show an addiction phenotype roughly matches the proportion seen in human populations of drug users (Deroche-Gamonet et al 2004, Vanderschuren and Everitt 2004). Electrophysiological analysis of "addicted" rats showed that synaptic plasticity in the ventral striatum was impaired and did not recover as in "non-addicted" animals (Kasanetz et al 2010). In studies of rats with extended access to cocaine and with gradually increasing intake of the drug, molecular analysis revealed that two competing pathways were activated in the dorsal striatum (Hollander et al 2010, Im et al 2010). Identification of these key pathways only in rats with extended access to cocaine suggests that an imbalance between these signaling pathways could generate the addicted state and perhaps be responsible for the aberrant plasticity previously seen in the ventral striatum. Whether the same pathways are involved in opiate addiction has, however, not been shown. A later study (Daglish et al 2003) has confirmed that cue exposure alone activates not only the anterior cingulate cortex but also the orbitofrontal cortical regions. These data support the idea that areas of brain activation are similar in both the response to a drug and cues associated with a drug and are centered on the mesolimbic pathway and a limited number of cortical areas. The rostral anterior cingulate cortex has been shown to play a key role in associative learning (Johansen and Fields 2004, Parkinson et al 2000), to respond to cues that lead to craving, and to also be crucial in the formation of associations between environmental context and pain (Johansen and Fields 2004), but not in the detection of pain itself. This also suggests that many of the areas of the brain thought to be specialized for storing or forming positive associations are also dealing with information related to similar but aversive events in the environment. There are, however, other regions of the nervous system, such as the spinal cord and primary nociceptive afferents, where local application of opiates will produce antinociception and do not support reinforcement. This is by no means a clean distinction but it brings into focus the idea that areas of the brain that support reinforcement generally produce analgesia and that this may not be coincidental. Close study of the behavior of knockout mice, however, reveals subtle changes in the ways that analgesia is reduced. However, stress-induced analgesia, which is known to involve the release of endogenous opioid peptides 360 Section Two Assessment and Psychology of Pain A Traditional view of cancer and non-cancer pain treatment with opioids Pain Cancer Inc. There is good evidence that endogenous opiate-mediated analgesia is generated in situations in which ongoing pain might distract from more important behavior judged to produce a greater chance for survival (Fields 2004). Naloxonereversible analgesia is induced in male rodents by the presence of a predator or an aggressive conspecific, and both conditioned analgesia (produced by associating a specific environmental cue with pain) and stress-induced analgesia (induced by a brief cold water swim) are reversible with naloxone (Miczek and Winslow 1987, Kavaliers and Colwell 1991, Segato et al 1997, Dutta et al 2001). The expectation of receiving opiate analgesia (placebo) produces a naloxone-reversible analgesia, presumably caused by antagonizing the observed binding of enkephalins to many of the brain areas that are activated during painful stimulation (Petrovic et al 2002). For example, feeding of sucrose to human infants and animals, as well as the anticipation of food by hungry adult rodents, produces a naloxone-reversible analgesia (Segato et al 1997). In other words, discomfort or pain can be blunted by activation of the endogenous pain suppression systems when attainment of positive goals such as food or sex is thought to be more important for the animal. The decision to activate endogenous pain pathways must be balanced by ongoing knowledge of the motivational state of the animal and against the anticipation of possible injury. In such situations an endogenous inhibitory pain system could be activated to reduce pain during the period of foraging and food ingestion demanded by the motivational state of hunger. Given the close relationship between motivational states and the experience of pain, is there any explanation why addictive states seem less likely to develop against a background of ongoing pain It is clear from clinical practice that tolerance and dependence are experienced as a result of chronic opiate treatment and are therefore unlikely to contribute to progression to the addicted state. However, the passive nature of a patient receiving opiate treatment in a hospital setting has been emphasized (Wise 2002), thus suggesting that associations between drug taking, contextual cues, and pain relief are unlikely to be made in this context. The drug habit that underpins the addicted state is built on positive experience with the drug and associations with drug paraphernalia, drugrelated environmental cues, and so on and would be unlikely to develop in a hospital environment. If the development of sensitization to opiates is under similar environmental constraints, this would account for the lack of any increase in the "incentive salience" or craving for the drug. Diagrams illustrating the shift in accepted opioid treatment of cancer and chronic non-cancer pain. A, the traditionally held view in which cancer pain and non-cancer (Non-ca) pain are regarded as different entities with different outcomes with respect to opioid treatment. The fear of chronic non-cancer pain leading to addiction, dependence, and ineffective relief is contrasted with the cancer pain, for which treatment with opioids is accepted as not leading to addiction. B, the consensus view (Dutta et al 2001, Petrovic et al 2002), in which cancer pain and non-cancer pain are part of chronic pain syndromes, for which opioids may be an appropriate treatment. Other aspects of opioids such as addiction appear to be rare in either group, although psychological dependence and pseudo-addiction may occur. Thus, in chronic pain at least, ongoing pain appears to prevent activation of the mesolimbic system. A more recent insight has been to extend the opioid use in cancer pain relief programs to the management of chronic non-malignant pain. The success in improved pain management with occasional evidence of addiction and abuse has led to further refining of the paradigm (American Academy of Pain Medicine 2004, the Pain Society 2004;. Pain is a complex multimodal process that affects individuals in a variety of ways. Accordingly, all complex and chronic pain should be assessed in a systematic manner, with specialist multidisciplinary input if required and with regular reviews and mutually agreed management plans. The fear of addiction always looms large, fueled as it is by social fears, legal constraints on prescription, anecdote, and misunderstanding of tolerance, physical dependence, and true addictive behavior. However, there is now good evidence that opioids have their place in the treatment of any pain-acute, chronic, malignant, and non-malignant-but the onus is on assessment, review, and appropriate prescription (Kalso et al 2003). The Pain Society: Recommendations for the appropriate use of opioids for persistent non-cancer pain, London, 2004, the Pain Society. The Pain Society: Recommendations for the appropriate use of opioids for persistent non-cancer pain. A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners and the Royal College of Psychiatrists, the Pain Society, 2004. Depending on the nature of experiences and instructions provided, a placebo analgesic effect can be elicited acutely in a very large percentage of individuals in both experimental and clinical contexts. Placebo analgesia has been linked with activity in the prefrontal cortex, endogenous opioid release in both the descending antinociceptive systems and forebrain structures, and reduced responses to noxious stimulation in regions of the anterior cingulate and insular cortex, thalamus, and spinal cord that correlate with reported pain relief.
The pain produced by muscle tension may thus not be the same as the original pain; however, patients (and physicians) may not be able to discriminate between the two when administering medications 001mg is equal to order meclizine online. Preliminary evidence supports the role of respondent conditioning in chronic pain patients symptoms neuropathy purchase generic meclizine on line. The chronic back pain patients showed anticipatory high muscle tension in the arm in the preconditioning phase when the dead body was never followed by pain medicine and health purchase meclizine 25 mg without a prescription. Klinger and co-authors (2010) reported higher conditioning and unconditioned muscle tension responses in chronic back pain patients and in patients who reported tension-type headaches that were also related to higher pain levels treatment 3rd stage breast cancer order cheap meclizine on line. In fibromyalgia syndrome, altered trace and delayed eye blink conditioning, as well as altered emotional learning and decision making, have been reported (Nees et al 2010, Walteros et al 2011) administering medications 8th edition purchase 25mg meclizine with visa. These results (Klinger et al 2010) suggest that different types of conditioning processes may be abnormal in chronic pain patients, which may be important in inducing and maintaining pain medicine images buy meclizine 25 mg online. Effect of aversive and appetitive unconscious conditioning on sensory and affective perception of non-painful (white) and painful (blue) thermal stimuli. After aversive conditioning, non-painful and painful thermal stimuli were judged more intense and more unpleasant than when preceded by appetitive or neutral conditioning. The startle reflex was significantly increased only in the condition that used painful stimuli after the aversive conditioning. Similarly, Lethem and co-workers (1983) emphasized that chronic pain patients tend to focus their attention on impending pain and subsequently avoid many types of activity, thus fostering the development of disability and depression. Thus, psychological expectations may lead to modified behavior, which in turn produces physical changes leading to still further physical deconditioning. In the case of chronic pain, anticipation or prevention of pain may be sufficient for long-term maintenance of the avoidance behavior. These observations add support to the importance of active physical therapy, with patients progressively increasing their activity levels despite fear of injury and discomfort being associated with renewed use of deconditioned muscles. Disconfirmation of the expected and feared outcomes by exposure may help desensitize patients and will serve to reinforce performance of additional activities that had previously been feared and avoided. The importance of operant learning factors is discussed further in the following section. In addition to the anticipation of pain and associated physiological processes, the subjective evaluation of pain may be modified by its association with affective variables, such as positive, negative, or neutral emotional states. Wunsch and colleagues (2003) showed that aversive slides paired with a painful stimulus led to higher pain intensity ratings of the same painful stimulus than when appetitive or neutral slides preceded the painful stimulus. Both the characteristics of a person in pain (such as facial expressions of pain) and the characteristics of the observer (such as empathy) probably contribute to the observational learning of pain (Goubert et al 2011). Vaughan and Lanzetta (1980, 1981) first demonstrated that physiological responses to pain stimuli may be vicariously conditioned during observation of others in pain. Rickard (1988) found that children of chronic pain patients chose more pain-related responses to scenarios presented to them and were more external in their health locus of control than were children with healthy or diabetic parents. Modeling probably plays a part in the phenomenon of pain-prone families (families with a significantly elevated occurrence of pain problems). Christensen and Mortensen (1975), for example, reported that children show the same pain syndromes that their parents currently have rather than the pain problems that their parents had in their own childhood. In common clinical practice, the acquisition or extinction of pain-related behavior by means of modeling has received little attention. However, there are occasional indications for the role of modeling in treating pain problems in children, on burn units, and after surgery. Despite the great deal of data available on the modification of experimentally induced pain behavior by means of modeling in healthy people, few experimental results support the process of vicarious learning in chronic pain patients (although see the early observational study performed on a burn unit and reported by Fagerhaugh in 1975). Nor have any longitudinal studies of the development of pain syndromes been conducted in pain-prone families. Controlled studies are necessary to provide evidence of modeling as a factor in the development of chronic pain disorders. Expectancies and actual behavioral responses to nociceptive stimulation are based, at least partially, on previous learning history. This may contribute to the marked variability in response to objectively similar degrees of physical pathology noted by health care providers. These data suggest that the mere presence of pain leads to a more aversive evaluation of any type of non-painful bodily sensation. This might explain why chronic pain patients frequently complain about a host of physical symptoms and are often classified as suffering from somatization disorder. This suggests that learning also influences biochemical variables involved in the transmission of nociception, as well as antinociception. These learning processes could be used to enhance analgesic processes in states of chronic pain. Respondent conditioning explains the differential response to analgesic medication since placebo effects, which form a large portion of the effects of analgesics, are not only based on expectancy but also greatly determined by respondent conditioning. These results support the contribution of respondent factors in the maintenance and exacerbation of chronic pain syndromes. They also suggest that interventions designed to alter high levels of muscle tension and specifically stress reactivity, as well as the cognitive and emotional evaluation of pain, might be of great value in the treatment of chronic pain patients. Children acquire attitudes about health and health care and the perception and interpretation of symptoms and physiological processes from their parents and social environment. They also learn appropriate responses to injury and disease and thus may be more or less likely to ignore or over-respond to the normal bodily sensations that they experience. The culturally acquired perception and interpretation of symptoms determine how people deal with illness. This attention may have survival value, may help avoid experiencing more pain, and helps learn what to do about acute pain. Bandura (1977a) documented the important role of observational vicarious learning (modeling) in many aspects of life. By modeling, not only can new patterns of behavior be acquired, but existing responses can also be inhibited or disinhibited. It is obvious that expressions of pain attract a high degree of attention from observers. From an evolutionary perspective, it can be assumed that participant observation of pain behavior is of use for survival since it can aid in avoiding future pain and impart response possibilities for similar situations. Craig (1986, 1987) proposed that observation of other persons can also contribute to the development and maintenance of chronic pain syndromes. Models can have influence on the expression and localization Biobehavioral Model Preconditions for chronic pain include predisposing factors, precipitating stimuli, precipitating responses, and maintaining processes (Flor and Turk 2011). The existence of a physiological predisposition or diathesis involving a specific body system is the first component of a biobehavioral model. Biobehavioral model delineating the main factors contributing to the development and maintenance of chronic pain. The existence of persistent aversive external or internal stimuli (pain-related or other stressors) with negative meaning activates the sympathetic nervous system and muscular processes. Aversive stimuli may be characterized by excessive intensity, duration, or frequency of an external or internal stimulus. Inadequate or maladaptive behavioral, cognitive, or physiological repertoires of the individual to reduce the impact of these aversive environmental or internal stimuli are among the precipitating responses. An important role played by the cognitive processing of external or internal stimuli is related to the experience of stress and pain, for example, increased perception, preoccupation, and over-interpretation of physical symptoms or inadequate perception of internal stimuli, such as muscle tension levels. Moreover, the nature of the coping response, such as active avoidance, passive tolerance, or depressive withdrawal, may determine the type of problem that develops, as well as the course of the illness. Subsequent maladaptive physiological responding, such as increased and persistent sympathetic arousal and muscular reactivity, as well as sensitization of central structures, including the cortex, may induce or exacerbate pain episodes. Learning processes in the form of respondent conditioning of fear of activity (including social, motor, and cognitive activities), social learning, operant learning of pain behavior, and operant conditioning of pain-related covert and physiological responses, as described above, make a contribution to the chronicity of pain. In short, a biobehavioral model places greatest emphasis on the role of learning factors in the onset, exacerbation, and maintenance of pain in patients with persistent pain problems. A range of factors predispose individuals to the development of chronic or recurrent acute pain; however, predisposition is necessary but not sufficient. In addition to anticipation, avoidance, and the contingencies of reinforcement, cognitive factors, in particular, are of central importance in understanding chronic pain. Conditioned reactions are viewed as self-activated on the basis of learned expectations, as well as automatically evoked. The critical factor, therefore, is not that events occur together in time but that people learn to predict them and to summon appropriate reactions (Turk et al 1983). The primary focus of a biobehavioral model is thus on the patient rather than on symptoms and pathophysiology. From this perspective, assessment and treatment of patients with persistent pain require a broader strategy than those based on the previous dichotomous models that examine and address the entire range of psychosocial and behavioral factors, in addition to biomedical ones (Turk and Rudy 1989). The biobehavioral perspective on pain management focuses on providing patients with techniques to gain a sense of control over the effects of pain on daily living, as well as actually modifying the affective, behavioral, cognitive, and sensory facets of the experience. Behavioral experiences help show patients that they are capable of more than they assumed by increasing their sense of personal competence. Our assumption is that long-term maintenance of behavioral changes will occur only if the patient has learned to attribute success to personal efforts. There are suggestions that these treatments can result in changes in beliefs about pain, coping style, and reported pain severity, as well as direct behavior damage and pain report. The more recent conceptualizations discussed view pain as a perceptual process resulting from nociceptive input and its modulation on a number of different levels in the central nervous system and not as being directly proportional to nociceptive input. Pain is a subjective, perceptual experience, 272 Section Two Assessment and Psychology of Pain learning, memory, and failure to extinguish aversive memory traces as important factors in pain chronicity. Pain has become a vigorous research area, and the explosion of information will surely lead to refinements in the biobehavioral view and advances in clinical management. As was noted, the current state of knowledge suggests that pain must be viewed as a complex phenomenon that incorporates physical, psychosocial, and behavioral factors. Failure to incorporate each of these factors will lead to an incomplete understanding. The range of psychological variables that have been identified as being of central importance in pain were reviewed, along with current understanding of the physiological basis of pain.