Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The central nervous system in mammals is able to react to painful stimuli at many levels that are involved in transmission, modulation and sensation of pain. Endogenous opioid peptides and their receptors are located at key points in pain pathways, and response to pain can be modulated by local application of opioids at many sites. Mechanisms of opioid analgesia at peripheral, spinal, medullary and midbrain levels are only incompletely understood; forebrain systems are even less appreciated. Local circuits in the spinal dorsal horn play a critical role in processing nociceptive afferent input and in mediating the actions of descending pain modulating systems. 2. The opioid receptors, recently cloned, exert their effects by activating G protein coupled effector systems, such as ion channels and second messenger systems. Although the receptor most commonly associated with pain relief is the mu-receptor, specific delta- and kappa-agonists can also mediate antinociception at spinal and supraspinal sites. Acute effects of opioids on target neurons are inhibitory, but excitatory effects have also been reported. 3. Noxious stimulation increases neuronal activity and modulates expression of genes, including immediate-early genes and neuropeptide (i.e. opioid) genes at spinal and supraspinal levels of the somatosensory system. Opioid drugs and endogenously released opioid peptides can modulate signal transduction mechanisms and intracellular processes that lead to alterations in protein phosphorylation and gene expression. These effects of opioids at the cellular level may underlie the mechanisms of pre-emptive analgesia and neuroplastic changes such as tolerance, dependence, sensitization, hyperalgesia, adaptation, addiction, and modulation of pain memories.
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PMID:Opioids and pain. 858 88

Much is known about opioid metabolism, which is critical in administering these agents to the elderly. Fear of addiction and tolerance are the major barriers to their use among patients as well as health-care professionals. Addressing these issues early in the initiation opioid therapy will help to alleviate these concerns. Once therapy with an opioid is initiated, the role of renal function is critical. Because many metabolites of the opioids are renally cleared and have activity either in analgesia or as undesired side effects, it is critical to be aware of the creatinine clearance (not just serum creatinine) in the elderly. The initiating doses of the opioids can be equal to that of younger patients, but the clinician should anticipate using a longer frequency of dosing interval or smaller doses during the course of therapy. Methadone, propoxyphene, and meperidine are not recommended for use in elderly people, because of the toxicity of their metabolites. Of all the unwanted effects of the opioids, the most difficult to deal with is that of constipation. Here, an aggressive approach using bowel stimulating laxatives is critical in order to prevent this problem. It is anticipated that a variety of newly formulated opioids will shortly be available for clinical use. Finally, as a better understanding of the neurophysiology of pain is gained, the clinician can anticipate having more analgesic opioids that target their receptors without agonist or antagonist effect on other opioid receptors. This will allow the clinician to better relieve pain with a minimum of unwanted side effects.
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PMID:Opioid analgesic drugs in the elderly. 885 41

Tramadol is a cyclohexanol derivative with mu-agonist activity. It has been used as an analgesic for postoperative or chronic pain since the late 1970s, and became one of the most popular analgesics of its class in Germany. International interest has been renewed during the past few years, when it was discovered that tramadol not only acts on opioid receptors, but also inhibits serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake. This review aims to provide a risk-benefit assessment of tramadol in the management of acute and chronic pain syndromes. Tramadol has been used intraoperatively as part of balanced anaesthesia. Such use is under discussion, however, as it was associated with a high incidence of intraoperative recall and dreaming, and postoperative respiratory depression has been described after intraoperative administration of high doses. Postoperatively, intravenous and intramuscular tramadol has been used with good efficacy. Analgesic doses were comparable with pethidine (meperidine) and 10 times higher than morphine. Nausea and vomiting were the most frequently reported adverse effects. In controlled studies, haemodynamic and respiratory parameters were only minimally impaired. The risk of severe respiratory depression in typical dosages is negligible in comparison with other opioids used for postoperative pain management. Tramadol has been used with good results for the management of labour pain without respiratory depression of the neonate. It was also effective for the treatment of pain from myocardial ischaemia, ureteric colic and acute trauma. Good results have been published for cancer pain management with tramadol in several studies. The potential for abuse or addiction seems to be minimal, and serious complications have not been reported. For patients with severe pain, the efficacy of morphine is superior, and most patients with adequate analgesia from tramadol had to be changed to a more potent opioid after a few weeks due to increased nociceptive input during tumour progression. Tramadol can be recommended as a safe and efficient drug for step II according to the World Health Organization guidelines for cancer pain management.
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PMID:A risk-benefit assessment of tramadol in the management of pain. 886 61

The controversy surrounding the long-term use of opioid drugs in patients with nonmalignant pain has intensified in recent years. This debate is driven by a new willingness to consider the potential benefits of an approach that has been traditionally rejected as invariably ineffective and unsafe. The published literature continues to be very limited, but a growing clinical experience, combined with a critical reevaluation of issues related to efficacy, safety, and addiction or abuse, suggests that there is a subpopulation of patients with chronic pain that can achieve sustained partial analgesia from opioid therapy without the occurrence of intolerable side effects or the development of aberrant drug-related behaviors. Future research must confirm this impression through controlled clinical trials and clarify those factors that may predict therapeutic success or failure. For the present, the clinician who contemplates this approach must have a clear grasp of the relevant issues and an understanding of the guidelines for treatment and monitoring that have proved useful in practice.
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PMID:Opioid therapy for chronic nonmalignant pain: a review of the critical issues. 886 56

Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.
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PMID:Differential opioid agonist regulation of the mouse mu opioid receptor. 899 64

There may be a population of patients subject to frequent headache and in whom optimal analgesic effect is obtained only by frequent but controlled use of opiate drugs and in whom adverse drug effects are minimal. It is emphasized again that the reality is that there are currently a large amount of opioids being prescribed for headache patients because of patients' demands. One of the major considerations for physicians prescribing such treatment is familiarity with the legal guidelines. The federal law requires physicians to register if they are to maintain or detoxify with opioids addicts defined as "any individual who habitually uses any narcotic drug so as to endanger the public morals, health, safety, or welfare, or is so far addicted to the use of narcotic drugs as to have lost the power of self-control with reference to his addiction." A subsequent regulation, however, stated that the law was not intended to impose any limitation on prescription of narcotics for intractable pain. There are also many different state regulations covering, for example, limitations on amounts to be prescribed and reporting of patients who are habitual narcotic users. Obviously, headache patients who request liberal amounts of opioids must be screened. There has been considerable recent effort to provide guidelines regarding which patients with nonmalignant pain might be poor candidates for opioid treatment by reason of both probable treatment failure and risk of drug overuse. Many of these guidelines are not relevant to headache patients in whom pain is rarely continuous and rarely demands scheduled analgesia, as is often the case with pain of other types. There is general agreement that any previous history of any type of substance abuse is an important indicator of danger of recurrence of such behavior. Evaluation of psychological state and personality structure is of great importance. The more evidence of emotional disturbance, the greater the danger both of poor results and of drug abuse. In the chronic daily headache population, treatment failure has been found to correlate with abnormalities on the Minnesota Multiphasic Personality Inventory (MMPI). It is possible that formal psychological testing prior to the prescription of opioid drugs will prove of value in identifying those headache patients at greatest risk for drug abuse. The importance of making opioid treatment part of a multifaceted pain program has been emphasized. Portenoy emphasizes the need for (1) careful discussion with the patient (and often family) of the potential side effects of the drugs, and (2) scrupulous monitoring of adherence to the appropriate dosage and maintenance of prescription by a single physician. The more psychological disturbance evidenced by the patient, the more the risk with failure of drug treatment and of drug abuse. Finally, the analgesic needs of the patient with frequent migraine are different from those of the patient with tension-type headache. Migraine infrequently occurs more than two or three times a week for any period and usually responds to ergotamine, dihydroergotamine, sumatriptan, or a phenothiazine. Addition of codeine or oxycodone for the occasional intractable attack may be needed. When demands in a migraine patient for opioids in amounts greater than 10 to 15 tablets per month occur, there is obvious cause for concern. The opioid agonist-antagonist butorphanol, now available in nasal inhalation form, is alleged to have low abuse potential because it tends to produce dysphoria (an unpleasant emotional state) rather than the euphoria of other opioids. It is therefore unscheduled. The drug, however, does have abuse potential, and the limits needed to be placed on its use are still uncertain. Markley recently recommended a restriction to not more than two bottles (30 treatments) per month. The population with frequent tension-type headaches presents the major problem. Large numbers of these patients use drugs--often in combination
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PMID:Opioids in headache treatment. Is there a role? 905 6

The long-term use of opioid analgesics in chronic nonmalignant pain has long been controversial. Rational discussion has been impeded by outdated research and myths regarding the risks of this therapy. Some of the misconceptions relate to the inappropriate use of the terms tolerance and addiction. Analgesic tolerance is a phenomenon in which exposure to the opioid itself causes the patient who has achieved analgesia to require a higher dosage to maintain the same level of effect. This appears to be very uncommon in the clinical setting. A need for dose escalation results from factors other than tolerance, including disease progression. Addiction is an association of psychological dependence and aberrant drug-related behaviors. Addiction to opioids in the context of pain treatment is rare in those with no history of addictive disorder. Clinicians need to become aware of the new findings regarding the low risk of addiction and tolerance in this setting.
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PMID:Clinical realities and economic considerations: special therapeutic issues in intrathecal therapy--tolerance and addiction. 929 8

Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In most species, including the humans, the circulating levels of melatonin, a substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at night, pinealectomy abolishes the analgesic effects of melatonin, and mu opioid receptor antagonists disrupt the day-night rhythm of nociception. It is believed that melatonin, with its sedative and analgesic effects, is capable of providing a pain free sleep so that the body may recuperate and restore itself to function again at its peak capacity. Moreover, in conditions when pain is associated with extensive tissue injury, melatonin's ability to scavenge free radicals and abort oxidative stress is yet another beneficial effect to be realized. Since melatonin may behave as a mixed opioid receptor agonist-antagonist, it is doubtful that a physician simply could potentiate the analgesic efficacy of narcotics such as morphine by coadministering melatonin. Therefore, future research may synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.
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PMID:Pineal opioid receptors and analgesic action of melatonin. 957 27

Opiates are potent analgesic and addictive compounds. They also act on immune responses, and morphine, the prototypic opiate, has been repeatedly described as an immunosuppressive drug. Pharmacological studies have suggested that the inhibitory action of opiates on immunity is mediated by multiple opioid receptor sites but molecular evidence has remained elusive. Recently, three genes encoding mu- (MOR), delta-, and kappa-opioid receptors have been cloned. To investigate whether the mu-opioid receptor is functionally implicated in morphine immunosuppression in vivo, we have examined immune responses of mice with a genetic disruption of the MOR gene. In the absence of drug, there was no difference between wild-type and mutant mice with regard to a large number of immunological endpoints, suggesting that the lack of MOR-encoded protein has little consequence on immune status. Chronic morphine administration induced lymphoid organ atrophy, diminished the ratio of CD4(+)CD8(+) cells in the thymus and strongly reduced natural killer activity in wild-type mice. None of these effects was observed in MOR-deficient mice after morphine treatment. This demonstrates that the MOR gene product represents a major molecular target for morphine action on the immune system. Because our previous studies of MOR-deficient mice have shown that this receptor protein is also responsible for morphine analgesia, reward, and physical dependence, the present results imply that MOR-targeted therapeutic drugs that are developed for the treatment of pain or opiate addiction may concomitantly influence immune responses.
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PMID:Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. 960 Sep 64

Peptide hormones and neurotransmitters play crucial roles in the maintenance of physiological function at both the cellular and organ level. Although peptide neuropharmaceuticals have enormous potential in the treatment of disease states, the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain either by enzyme degradation or by specific properties of the BBB. Peptides that act at opioid receptors are currently being designed for analgesia and to reduce the unwanted side effects associated with morphine, such as addiction and inhibition of gastric motility. It has been the focus of our group to produce stabile peptide analogues of Met-enkephalin, that lead to analgesia without side effects. In this paper we present the methodologies that have been used to elucidate the transport mechanisms of three peptides across the BBB. Using a primary endothelial cell culture model of the BBB, in situ perfusion, and kinetic analysis we show that D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) crosses the BBB via diffusion, [D-penicillamine2,5]enkephalin uses a combination of diffusion and a saturable transport mechanism, and biphalin ([Tyr-D-Ala-Gly-Phe-NH]2) uses diffusion and the large neutral amino acid carrier. Understanding BBB transport mechanisms for peptides will aid in the rational design of peptides targeted to the brain.
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PMID:Transport of opioid peptides into the central nervous system. 981 2


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