Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amitriptyline is a tricyclic antidepressant used to treat major depression and various neuropathic pain syndromes. This drug also causes cardiac toxicity in patients with overdose. We characterized the tonic and use-dependent amitriptyline block of human cardiac (hH1) Na(+) channels expressed in human embryonic kidney cells under voltage-clamp conditions. Our results show that, near the therapeutic plasma concentration of 1 microM, amitriptyline is an effective use-dependent blocker of hH1 Na(+) channels during repetitive pulses (approximately 55% block at 5 Hz). The tonic block for resting and for inactivated hH1 channels by amitriptyline (0.1-100 microM) yielded IC(50) values (50% inhibitory concentration) of 24.8 +/- 2.0 (n = 9) and 0.58 +/- 0.03 microM (n = 7), respectively. Substitution of phenylalanine with lysine at the hH1-F1760 position, a putative binding site for local anesthetics, eliminates the use-dependent block by amitriptyline at 1 microM. The time constants of recovery from the inactivated-state amitriptyline block in hH1 wild-type and hH1-F1760K mutant channels are 8.0 +/- 0. 5 (n = 6) and 0.45 +/- 0.07 s (n = 6), respectively. A substitution at either hH1-F1760K or hH1-Y1767K significantly increases the IC(50) values for resting and inactivated states of amitriptyline, but the increase is much more pronounced with the hH1-F1760K mutation. Because these two residues were proposed to form a part of the local anesthetic binding site, we conclude that amitriptyline and local anesthetics interact with a common binding site. Furthermore, at therapeutic concentrations, the ability of amitriptyline to act as a potent use-dependent blocker of Na(+) channels may, in part, explain its analgesic actions.
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PMID:Block of human heart hH1 sodium channels by amitriptyline. 1068 18

We have recently found that the infection with herpes simplex virus type-1 (HSV-1) of primary sensory neurons induces nociceptive hypersensitivity to noxious mechanical (hyperalgesia) and tactile stimulation (allodynia) in mice. In the present experiments, we determined the distribution of HSV-1 in the dorsal root ganglia and examined the effects of four analgesic agents on hyperalgesia and allodynia. HSV-1 was inoculated on the unilateral shin. HSV-antigen-positive cells were detected in the L4 and L5 dorsal root ganglia on days 5 and 7, but not day 3, post-inoculation. About 80% of the positive cells were small in size. Allodynia and hyperalgesia appeared on day 5 post-inoculation. Antinociceptive effects of analgesic agents were examined on day 6 post-inoculation. Morphine (1-5 mg/kg, subcutaneous) and gabapentin (10-100 mg/kg, peroral) dose-dependently inhibited both allodynia and hyperalgesia. Diclofenac (10-100 mg/kg, intraperitoneal) also produced antinociceptive effects, but there was a ceiling for the effect on hyperalgesia. Amitriptyline (3, 10 mg/kg, subcutaneous) did not affect allodynia and hyperalgesia. The results suggest that mechanical allodynia and hyperalgesia appeared when HSV-1 proliferated in the sensory neurons. This mouse model may be useful for studying the mechanisms of acute herpetic pain and anti-neuropathic pain agents.
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PMID:Pharmacological and immunohistochemical characterization of a mouse model of acute herpetic pain. 1100 Nov 78

The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin (5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.
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PMID:Central sensitization in tension-type headache--possible pathophysiological mechanisms. 1103 46

The tricyclic anti-depressant amitriptyline is widely used in the treatment of chronic tension-type headache. The aim of the present study was to investigate whether the analgesic effect is caused by a reduction of muscle pain or by a general reduction of pain sensitivity. Thirty-three non-depressed patients with chronic tension-type headache were treated with amitriptyline 75 mg/day and with the highly selective serotonin reuptake inhibitor citalopram 20 mg/day in a 32-week, double-blind, placebo-controlled, three-way crossover study. At the end of each treatment period, actual headache intensity and pericranial myofascial tenderness were recorded, pressure pain detection and tolerance thresholds were measured in the finger and in the temporal region and the electrical pain threshold was measured at the labial commissure. Amitriptyline reduced tenderness and headache intensity significantly more than placebo (P=0.01 and P=0.04, respectively). The reduction in tenderness could be ascribed solely to the group of patients who responded to amitriptyline treatment by at least 30% reduction in headache while tenderness was unchanged in non-responders. Amitriptyline did not affect pressure or electrical pain thresholds at any of the examined locations. Citalopram had no significant effect on any of the examined parameters. These findings indicate that amitriptyline elicits its analgesic effect in chronic myofascial pain by reducing the transmission of painful stimuli from myofascial tissues rather than by reducing overall pain sensitivity. We suggest that this effect is caused by a segmental reduction of central sensitization in combination with a peripheral anti-nociceptive action.
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PMID:Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache. 1107 46

There are currently no treatments available (beyond optimal control of hyperglycemia) that arrest or reverse progressive diabetic polyneuropathy. Consultation with a diabetologist is indicated for patients with poorly controlled disease and polyneuropathy. Immunotherapy for diabetic lumbosacral plexopathy has been advocated but is not supported to date by class 1 clinical trial evidence. Pharmacologic treatment for painful neuropathy may include topical anesthetics, capsaicin cream, anticonvulsants, tricyclic antidepressants, mexiletine, and opioids. Gabapentin, a newer anticonvulsant, has an attractive side-effect profile (a consideration in older patients) and has fewer interactions with other drugs. Amitriptyline may cause excessive sedation, postural hypotension, constipation, and urinary retention, but low evening doses (10 to 25 mg), slowly titrated upward, may offer relief from nocturnal pain. Opioids should not be withheld from patients with severe pain or with intolerance of or contraindications to other agents. A single physician should supervise their use.
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PMID:Diabetic Neuropathies. 1109 34

The treatment of migraine headache in children depends on the following: a) defining the underlying cause; b) the frequency of the attacks; and c) the severity of the disability produced by the pain. Any medication taken to relieve pain is most effective if taken at maximum dose at the onset of the headache. The dose should be the maximum recommended by weight or age. Triptans are also more effective if used early. Over-the-counter (OTC) analgesics are often effective in relieving pediatric headache and should be tried before prescription drug therapy is attempted. The more frequent a child's headaches are, the greater the danger that repeated doses of pain medications, including those purchased OTC, will lead to a chronic headache syndrome as the medication is reduced. Recurrent severe headaches, occurring more than once a week and resulting in interruption of normal activities or poor concentration, need to be treated with prophylactic medications taken daily so that the number of headaches can be reduced. Amitriptyline, propanolol, and periactin are the most frequently used drugs to block headaches, but valproate, verapamil, or other calcium channel blockers and other antidepressants are also useful. Biofeedback, relaxation, or cognitive therapies can also reduce headache frequency in children with both migraine and tension headaches. Headaches that are intractable to oral medication for the acute relief of pain may respond more rapidly to an efficiently absorbed drug administered by nasal spray or subcutaneously. The initial dose of an injectable drug should be given in a situation where a physician is immediately available. Recurrent headaches that have occurred over more than 6 months and that are associated with a normal neurologic examination are almost never caused by an intracranial lesion. Routine CT and MRI scans or an electroencephalogram (EEG) are generally unnecessary for these patients because these scans are rarely of value in these patients unless there is a history of another neurologic disorder or the headaches are focal, relentless, and worsening over time.
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PMID:Childhood Migraine Headache Syndromes. 1128 41

An axonal sensory neuropathy is a frequent complication in the course of HIV infection; more than 30% of all HIV-infected individuals will develop a polyneuropathy. Low CD4 cell counts and high HIV RNA loads increase the risk. This neuropathy causes pain, paresthesias and burning sensations and/or numbness in the feet, which sometimes occurs in the hands as well. Neurological examination reveals sensory deficits in a stocking and glove distribution and depressed or absent ankle reflexes, without severe paresis. The cause of the sensory neuropathy is unknown. Either the HIV infection or certain other infections, for example cytomegalovirus, may play a role in the pathogenesis; vasculitis may be a process associated with this. Some antiretroviral drugs within the nucleoside analogue group cause a neuropathy but the pathogenesis of this remains unclear. Amitriptyline, tramadol and carbamazepine can be used for symptomatic treatment. The efficacy of lamotrigine and gabapentin has yet to be confirmed.
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PMID:[Sensory neuropathy in HIV infection: pathogenesis and therapy]. 1133 55

Three independent studies utilizing transcutaneous electrical nerve stimulation to relieve diabetic peripheral neuropathic pain were reviewed. The proprietary equipment, an H-wave machine, administered all electrotherapy. The first two studies assessed the efficacy of electrotherapy alone and electrotherapy with amitriptyline. The treated electrotherapy group reported an overall greater reduction of symptoms, 52% with 2-3 weeks of active treatment. Amitriptyline alone produced a 26% reduction of pain after 4 weeks. The addition of active electrotherapy to amitriptyline produced a 66% reduction of pain. The final study looked at patients who have utilized electrotherapy for over one year. A reported 44% improvement of symptoms was attained with continuous electrotherapy treatment. The data also suggested that a maintenance treatment protocol for long-term pain relief would have to be developed.
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PMID:Transcutaneous electrostimulation: emerging treatment for diabetic neuropathic pain. 1147 9

The post-receptorial mechanisms of the analgesic action of amitriptyline and clomipramine, two tricyclic antidepressants, were investigated in the mouse hot plate test by using an antisense strategy. Mice were injected i.c.v. with antisense oligonucleotides (aODN), complementary to the sequence of the mRNA sequence of the alpha-subunit of Gi1, Gi2 and Gi3-proteins, 18-24 h prior to the hot plate test. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha dose-dependently reduced the analgesia induced by both amitriptyline (15 mg/kg s.c.) and clomipramine (25 mg/kg s.c.). This antagonistic effect disappeared 7 days after the end of the i.c.v. treatment, indicating the absence of irreversible damage or toxicity. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha, at the active doses, did not modify the animals' pain threshold, indicating the absence of any hyperalgesic effect. Amitriptyline, clomipramine and the aODN employed, at the maximal effective doses, did not produce any alteration of motor coordination of the mice, as revealed by rotarod experiments, and spontaneous motility, as revealed by the Animex apparatus. These results indicate that amitriptyline and clomipramine induce their analgesic effect by activating all three subtypes of the Gi-proteins.
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PMID:Amitriptyline and clomipramine activate Gi-protein signaling pathway in the induction of analgesia. 1186 27

Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. However, adverse effects are a major problem. Venlafaxine has no anticholinergic effects and could have a better compliance. The aim of the study was to evaluate the effectiveness of venlafaxine in neuropathic pain. The study was a randomized, double-blind, crossover comparison of venlafaxine and inactive placebo. The study lasted 10 weeks. The number of tablets (18.75 mg) taken daily was increased by one at a 1 week interval. Pain intensity and pain relief were registered daily by a diary and by a questionnaire and a computer program (Painscreen) on each visit. Adverse effects were evaluated with the diaries and a 10-item list on each visit. Also, anxiety and depression were measured on each visit. Venous blood samples were collected before the treatment and at 4 weeks for the determination of the serum levels of venlafaxine and its three metabolites. Thirteen patients were analysed. The average daily pain intensity as reported in the diary (primary outcome) was not significantly reduced by venlafaxine compared with placebo. However, the average pain relief (diary) and the maximum pain intensity (retrospective assessment by the computer program) were significantly lower with venlafaxine compared with placebo. Anxiety and depression were not affected. Adverse effects did not show significant differences between treatments. The two poor responders had low venlafaxine concentrations whereas the two slow hydroxylizers had high venlafaxine concentrations and excellent pain relief. Thus, higher doses could be used in order to improve pain relief.
Eur J Pain 2002
PMID:Venlafaxine in neuropathic pain following treatment of breast cancer. 1188 24


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