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PubMed1995

Effects of amitriptyline on rat plasma and brain content of monoamine precursors and other large neutral amino acids.

Amitriptyline caused decreased concentrations in rat plasma of the amino acids tyrosine and tryptophan, which are precursors to monoaminergic neurotransmitters, and also of those other large neutral amino acids (LNAAs) (valine, phenylalanine, leucine and isoleucine) with which tyrosine and tryptophan compete for the carrier-mediated transport from plasma into the brain. The various LNAAs were, however, not decreased to the same extent. Thus, the relative concentrations, calculated as the ratio of each one of them to the total concentration of LNAAs, were also influenced by amitriptyline. The relative concentrations of tryptophan were decreased while the relative concentrations of phenylalanine and leucine were increased. Those of tyrosine, valine and isoleucine were not influenced by amitriptyline. The relative concentrations of the LNAAs in plasma are considered to be of importance to how much of each of them that will be transported into the brain. Based on this assumption one would have expected that the amitriptyline-induced changes in the relationships between different LNAAs would have caused changes in their brain concentrations in accordance with their relative concentrations in plasma. However, amitriptyline caused decreased concentrations of all LNAAs in rat whole brain. This finding cannot be explained by altered relationships between the LNAAs but must be explained by other mechanisms. Nevertheless, this effect of amitriptyline on brain LNAA concentrations might be of importance to monoamine function.

Adrenergic Uptake Inhibitors↗
PubMed2001

Amitriptyline enhances the central component of physiological tremor.

OBJECTIVES: Postural tremor is a regularly encountered side effect of amitriptyline which can be strong enough to cause discontinuation of therapy. The aim was to characterise amitriptyline induced tremor and to assess if the central or reflex component of physiological tremor was modulated by this drug. METHODS: The postural hand tremor was measured in 15 patients on a clinical rating scale, by power spectral analysis of accelerometer, forearm flexor, and extensor EMG before and after the beginning of amitriptyline treatment for major depression or chronic pain syndrome. A coherence analysis between flexor and extensor muscles on the same side was performed. RESULTS: There was a clinically visible increase in postural tremor in a third of these patients. The tremor amplitude measured by accelerometer total power increased in every patient under amitriptyline. The EMG synchronisation as reflected by significant peaks in the flexor or extensor spectrum generally occurring at higher frequencies (8-18 Hz) than the accelerometric tremor frequencies (6-11 Hz) did not change. The number of patients with a significant flexor-extensor coherence in the 7-15 Hz range increased significantly under amitriptyline, the frequency bands of significant coherence corresponded with the EMG frequencies, and both were independent of changes to the hand's resonant frequency by added inertia. CONCLUSIONS: An enhancement of postural tremor under amitriptyline is a common phenomenon although not always clinically apparent. The increase in EMG-EMG coherence indicates an increased common central drive to the motor units as its frequency is not influenced by peripheral resonance or reflex mechanisms. This is the first account of a drug induced enhancement of the central component of physiological tremor.

Amitriptyline↗
PubMed1989

Acute amitriptyline effects on parasympathetic-evoked rat saliva.

The present study was undertaken to investigate the acute effects of amitriptyline on salivary secretion evoked by electrical stimulation of the parasympathetic innervations of rat salivary glands. Single intravenous injections of amitriptyline (0.1-1 mg/kg) caused a dose-related decrease in flow and Na concentration of saliva from both parotid and submandibular glands. However, the only effect on K concentration was a slight increase when the salivary flow was almost completely inhibited. Amitriptyline increased the Ca concentration of nerve-evoked submandibular saliva, but had no effect on the Ca concentration of similarly evoked parotid saliva. However, amitriptyline (0.5 and 1 mg/kg) increased the protein concentration of both kinds of saliva. Amylase activity of parotid saliva was also moderately increased by amitriptyline. These effects were similar to those observed with atropine, a known cholinergic receptor antagonist. These results suggest that amitriptyline, like atropine, reduces parasympathetic-evoked salivary secretion by blocking cholinergic receptors.

Amitriptyline↗
PubMed1997

Inhibitory effect of amitriptyline on contraction of the rat isolated trachea.

The effects of amitriptyline, a tricyclic antidepressant, on contractile responses to exogenously applied acetylcholine, endothelin 1 and high K+ were examined in the rat isolated trachea. Amitriptyline (0.3-30 mumol/l) produced a shift to the right of the logarithmic acetylcholine concentration-contraction curve without affecting the maximum contraction. Amitriptyline (10-100 mumol/l) significantly reduced the maximal contractile response to endothelin 1. The IC50 values were 10.3 and 30.2 mumol/l for inhibition of the submaximal contractile response to 1 mmol/l acetylcholine and to 50 nmol/l endothelin 1, respectively. Amitriptyline inhibited the high K+ (60 mmol/l)-evoked contraction with an IC50 of 0.225 mumol/l. The inhibitory effect of amitriptyline was unchanged by the K+ channel blockers, charybdotoxin (100 nmol/l) and glibenclamide (up to 10 mumol/l). These results indicate that amitriptyline could antagonize the effect of acetylcholine and also exert direct inhibitory effect on muscle contraction of the rat trachea as a nonselective muscle relaxant.

Acetylcholine↗
PubMed1997

Metabolism of the tricyclic antidepressant amitriptyline by cDNA-expressed human cytochrome P450 enzymes.

The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)-10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with Km values in the range of 5-13 mumol/l, whereas the affinities of 1A2, 3A4 and 2C9 were somewhat lower with Km values ranging from 74 to 92 mumol/l. CYP 2C19 displayed the highest reaction capacity per mole with Vmax equal to 475 mol h-1 (mol CYP)-1. The other enzymes had Vmax values in the range of 90-145 mol h-1 (mol CYP)-1. Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the metabolism.

Amitriptyline↗
PubMed2002

Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study.

BACKGROUND AND PURPOSE: We performed a double-blind, placebo-controlled study to investigate the effectiveness of amitriptyline for the prophylactic treatment of patients with acute thalamic stroke in preventing central poststroke pain. METHODS: Subject received, in a randomized sequence, either amitriptyline titrated from 10 to 75 mg in extended-release form or placebo over a therapy period of 365 days. We documented the time when pain developed; the intensity, type, site, and distribution of pain; and the presence/absence and type of allodynia. RESULTS: Thirty-nine patients (23 women and 16 men; age range, 36 to 68 years) with central poststroke pain participated. The placebo group showed a pain rate of 21% within 1 year after the diagnosis of thalamic stroke compared with 17% in the group under prophylactic treatment with amitriptyline. Average (SE) time to pain was 318 (23) days for patients in the placebo group and 324 (24) days for patients in the amitriptyline group. CONCLUSIONS: With the achieved sample sizes of this study and a pain rate of approximately 21% in the placebo group, any near-perfect pain protection would have been detected. Near-perfect pain protection, in this context, refers to pain in <2.4% of the recruited patients treated with amitriptyline or in approximately 89% of placebo-treated patients. Larger studies are recommended to test the hypothesis that prophylactic amitriptyline reduces but does not completely prevent central poststroke pain.

Acute Disease↗
PubMed1996

Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects.

OBJECTIVE: This study was done to compare the effects of 6-week treatment with amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) regulation in elderly depressed patients and age-matched comparison subjects. METHOD: A combined dexamethasone-suppression/CRH-stimulation (dexamethasone/CRH) test was administered before initiation of amitriptyline treatment and at the end of weeks 1, 3, and 6 of treatment. Thirty-nine depressed inpatients, mean age = 69 years, completed the study. Fourteen normal volunteers, mean age = 67 years, served as comparison subjects. RESULTS: In relation to the comparison subjects, the depressed patients had a profoundly abnormal HPA response, in particular an exaggerated cortisol release in the dexamethasone/CRH test. This abnormality began to disappear after 1 week of treatment with amitriptyline. In contrast, amitriptyline did not affect neuroendocrine regulation in the comparison subjects at any time during the test period. CONCLUSIONS: The data suggest that amitriptyline affects HPA regulation in hypercortisolemic depression only, and they raise the possibility that normalization of its feedback control is related to the antidepressive effect of amitriptyline.

Aged↗
PubMedDate not supplied

Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study.

AIMS AND BACKGROUND: Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain. METHODS: Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded. RESULTS: No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P < 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P < 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects. CONCLUSIONS: In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned.

Aged↗
PubMed1984

Lidocaine and amitriptyline interaction during experimental haemoperfusion.

Displacement of amitriptyline by lidocaine was studied during haemoperfusion (HP) in five beagle dogs. Clearance of amitriptyline during HP was 0.93, although the amount of amitriptyline removed was only 2% of the given dose. Lidocaine does therefore not improve amitriptyline yield during HP. Clearance of lidocaine during HP was 0.99. Almost 13% of the lidocaine given intravenously was removed by HP. Lidocaine did not improve myocardial performance during HP in amitriptyline-intoxicated dogs. At necropsy the highest concentrations of amitriptyline in this model were found in the brain and the lung. The amitriptyline/nortriptyline ratio was lowest in the liver and lung, suggesting that these two organs are major sites of metabolism.

Amitriptyline↗
PubMed2002

Amitriptyline has a dual effect on the conductive properties of the epithelial Na channel.

This study was undertaken with the aim of testing the action of amitriptyline on the epithelial Na channel (ENaC), which belongs to the same family (Deg/ENaC) as ASICs (acid-sensing ion channels) and many other putative members in the brain. We assumed that, having a common protein structure, characterization of the amitriptyline-ENaC interaction could help to elucidate the analgesic mechanism of this tricyclic antidepressant. Na-channel characteristics were derived from the analysis of blocker-induced lorentzian noise produced by amiloride. The effect of amitriptyline, present in the mucosal bathing solution, on the transepithelial short-circuit current (I(sc)) and conductance (G(t)), and on the blocker-induced noise of apical Na channels, was studied on isolated ventral skin of the frog Rana ridibunda. Amitriptyline exerted a dual effect on the macroscopic short-circuit current and conductance of the epithelia, increasing these two parameters in the concentration range 0.1-50 microM, while at higher concentrations (100-1000 microM) it showed an inhibitory action. The decrease in the association rate (k(01)) of amiloride to the apical Na channels from 15.6+/-4.2 microM(-1) s(-1) in control Cl-Ringer to 7.4+/-1.7 microM(-1) s(-1) at 200 microM amitriptyline in a concentration-dependent manner suggests a competitive binding of amitriptyline to the pyrazine ring binding site for amiloride.

Algorithms↗
PubMed1987

Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood.

In a randomized, double-blind crossover study, 29 patients with painful diabetic neuropathy received 6 weeks of amitriptyline and 6 weeks of an "active" placebo that mimicked amitriptyline side effects. Amitriptyline was superior to placebo in relieving pain in weeks 3 through 6. Both steady, burning pain and lancinating pains were relieved. Patients able to tolerate higher amitriptyline doses reported greater relief, through the maximum dose of 150 mg nightly. Amitriptyline analgesia was similar in depressed and nondepressed subgroups and was not associated with mood improvement. We conclude that amitriptyline relieves pain in diabetic neuropathy; this effect is independent of mood elevation.

Adult↗
PubMed2003

Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats.

UNLABELLED: Amitriptyline, a tricyclic antidepressant, has potent local anesthetic properties. However, there is no report of cutaneous analgesic effects after transdermal application. We report here that transdermally applied amitriptyline is more potent than lidocaine in providing cutaneous analgesia in rats. Solutions of amitriptyline base in 50, 100, and 500 mM concentrations were applied as a patch to rats, and their effects were compared with those of lidocaine base at the same concentrations and of the vehicle alone (45% water, 45% isopropyl alcohol, and 10% glycerin). Rats in each test group developed a concentration-dependent cutaneous analgesic block in the areas to which the drugs were applied; however, amitriptyline produced a longer block than lidocaine at the same concentration. The development of amitriptyline as a longer-lasting topical analgesic may improve our ability to treat chronic pain, such as neuropathic pain and neuralgia, and to prevent pain in procedures such as venipuncture. IMPLICATIONS: The tricyclic antidepressant amitriptyline, often used perorally for the management of chronic pain, is shown here to be more potent than lidocaine in providing cutaneous analgesia when applied transdermally with an occlusive dressing in rats.

Administration, Cutaneous↗
PubMed2002

Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression.

The relationship between serum concentration (C(s)) of amitriptyline and its therapeutic effect in depression has been investigated frequently over the last 3 decades; however, the results were controversial and no consensus was reached. Therefore, we have performed a comprehensive survey and meta-analysis of the subject. All relevant literature was included, and the design of studies on the serum concentration-therapeutic effect relationship (SCTER) of amitriptyline was evaluated. Pooled original data from SCTER studies with adequate design were analysed by various statistical methods: regression analysis of therapeutic effect and C(s); comparison of the mean therapeutic effect in various ranges of C(s); dichotomisation of outcome and analysis according to sensitivity of receiver operation curves; frequency of responders and nonresponders in ranges determined by points of sensitivity; analysis of the distribution of C(s) in responders and nonresponders; logistic regression of responders and nonresponders with C(s) and other independent variables; calculation of effect size (g) and mean effect size (g(m)). Forty-five SCTER studies of amitriptyline were identified, and 27 studies met the minimum criteria of adequate study design. Inadequate study design predicted the finding of no SCTER. Analysis of the pooled data from studies with adequate design confirmed a therapeutic window of the sum of C(s) of amitriptyline and its active metabolite nortriptyline of about 80 to 200 microg/L. A moderate and significant positive g(m) (0.538, 95% confidence interval 0.167 to 0.909) was calculated for treatment with C(s) within the therapeutic window in comparison with treatment with C(s) outside the therapeutic window (19 studies with adequate design and original data available, n = 583). In conclusion, the evidence for a biphasic SCTER of amitriptyline in depression is considerably improved, and the results may help to find a consensus in the future. However, the clinical benefit of therapeutic drug monitoring of amitriptyline can only be demonstrated in a controlled and randomised study. Furthermore, the results provide further evidence that antidepressants at optimum C(s) are superior to placebo in the treatment of depression.

Amitriptyline↗
PubMed2003

Randomized controlled trial of the efficacy of short-term amitriptyline administration for treatment of acute, nonobstructive, idiopathic lower urinary tract disease in cats.

OBJECTIVE: To determine whether short-term amitriptyline administration would be efficacious in the treatment of acute, nonobstructive, idiopathic lower urinary tract disease in cats. DESIGN: Randomized controlled trial. ANIMALS: 31 untreated male and female cats with acute, nonobstructive, idiopathic lower urinary tract disease. PROCEDURES: Cats were treated with amitriptyline (5 mg/d; n = 16) or a placebo (15) for 7 days and monitored for pollakiuria, hematuria, and adverse events. Cats were reexamined 1 month after treatment, and owners were interviewed by telephone 6, 12, and 24 months after treatment. RESULTS: 2 amitriptyline-treated cats were excluded from analyses because of acquired urinary tract infection. Clinical signs resolved by day 8 in 8 amitriptyline-treated and 10 control cats. There were no apparent differences in likelihood or rate of recovery from pollakiuria or hematuria between groups. Overall, clinical signs recurred significantly faster and more frequently in amitriptyline-treated than control cats. However, after excluding recurrences within 21 days of treatment, risk of recurrence was similar in both groups. Increasing age was significantly associated with increased likelihood and rate of recovery from hematuria and with decreased risk of recurrence of signs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that short-term amitriptyline treatment has no benefit in terms of resolution of pollakiuria and hematuria in cats with idiopathic lower urinary tract disease and may be associated with an increased risk of recurrence.

Acute Disease↗
PubMedDate not supplied

A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy.

An 8-week double-blind, multicenter, parallel study compared the safety and efficacy of topical capsaicin and oral amitriptyline in patients with painful diabetic neuropathy involving the feet. Two hundred thirty-five patients were randomized to treatment with either capsaicin cream or amitriptyline capsules. Capsaicin-treated patients received inactive capsules, and amitriptyline-treated patients applied vehicle cream. A visual analogue scale of pain intensity and measurements of interference by pain with functional activities were recorded at onset and at 2-week intervals. A visual analogue scale of pain relief and physicians' global evaluation assessed changes in pain status from baseline. Topical capsaicin and oral amitriptyline produced equal and statistically significant improvements in pain over the course of the study. By the end of week 8, 76% of patients in each group experienced less pain, with a mean reduction in intensity of more than 40%. By the end of the study, the interference with daily activities by pain had diminished significantly (P = .001) in both groups, including improvements in sleeping and walking. No systemic side effects were observed in patients treated with topical capsaicin. Most patients receiving amitriptyline experienced at least one systemic side effect, ranging from somnolence (46%) to neuromuscular (23%) and cardiovascular (9%) adverse effects. Topically applied capsaicin is an equally effective but considerably safer alternative to amitriptyline for relief of the pain of diabetic neuropathy.

Administration, Oral↗
PubMed2001

A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain.

In a preclinical study we found fluoxetine alone to induce a serotonin-mediated, dose-dependent antinociceptive effect in the mouse hot plate assay. In the present study we evaluated the clinical implication of these findings, comparing the efficacy of fluoxetine with that of amitriptyline for musculo-skeletal pain. Forty non-depressed patients, suffering from low back pain and whiplash associated cervical pain were enrolled in a randomized, six-week, "blind-rater" study, comparing the analgesic effect of amitriptyline (50-75 mgs/day) with that of fluoxetine (20 mgs/day). Twenty patients were randomly assigned to the amitriptyline group, and twenty to the fluoxetine group. Visual analogue and verbal rating scales were used for the assessment of pain intensity and pain relief. Thirty-five patients concluded the study. Moderate or good relief of pain was reported by 14 of the 17 patients (82%) in the amitriptyline group, and by 14 of the 18 patients (77%) in the fluoxetine group. The difference in responses between amitriptyline and fluoxetine was not statistically significant. In our study, fluoxetine relieved low back pain and whiplash associated cervical pain with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the tricyclic antidepressants' side effects.

Adolescent↗
PubMed1991

[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats].

The effects of two antidepressant drugs, amoxapine and amitriptyline, that belong to distinct chemical classes, have been examined on various biochemical parameters related to serotoninergic and opioidergic neurotransmission in the rat brain and spinal cord. In vitro binding studies showed that both amoxapine and amitriptyline interact in the nanomolar range with 5-HT2 receptors labelled by [3H]ketanserin in cortical membranes. By contrast, neither amoxapine nor amitriptyline can be considered as possible ligands of 5-HT1A and 5-HT1B receptors because their affinities for these sites are in the micromolar range (or even worse). Interestingly, amoxapine binds with a good affinity (IC50 = 0.30 microM) to 5-HT3 receptors labelled by [3H]zacopride in cortical membranes. Complementary experiments using the 5-HT3-dependent Bezold-Jarisch reflex confirmed that amoxapine really acts in vivo as a 5-HT3 antagonist (IC50 = 50 micrograms/kg i.v.), whereas amitriptyline is essentially inactive on 5-HT3 receptors. The second part of this study consisted of looking for possible changes in central 5-HT receptors 24 h after either a single or a repeated (for 14 days) treatment with amoxapine (10 mg/kg i.p. each day) or amitriptyline (10 mg/kg i.p.). A marked decrease in the density of 5-HT2 receptors was found in the cerebral cortex in both treatment groups. By contrast, neither 5-HT1A nor 5-HT1B receptors were significantly affected in any brain region studied. Finally we explored whether acute and/or chronic administration of amoxapine or amitriptyline affected the levels of opioid peptides and the mu and delta classes of opioid receptors in various regions of the brain and the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed2006

Efficacy of amitriptyline for treatment of somatoform pain disorder in the orofacial region: A case series.

AIMS: To determine the efficacy of amitriptyline and the optimal dosage for treating a somatoform pain disorder in the orofacial region. METHODS: Thirty outpatients with orofacial pain who fulfilled the criteria of pain disorder were recruited for the study. Twenty-three patients had specific precipitating events in their past history, which they considered to be the origin of the pain. Amitriptyline was administered and the dose was gradually increased up to a daily dose of 250 mg. The response to treatment was evaluated using a numeric rating scale and the Clinical Global Impression Scales. RESULTS: Five patients dropped out and 25 patients (83%) completed the trial. Twenty-two patients became pain free or nearly pain free, while 3 patients who also completed the study did not respond at all, even though they took a daily dose of 250 mg amitriptyline. For responders, the mean daily dose of amitriptyline was 77.5 +/- 51.5 mg (range, 10 to 200 mg). Four patients (16%) obtained pain relief with a daily dose of less than 50 mg, while 3 patients (12%) needed a daily dose of 150 mg or more for pain relief. Adverse side effects were observed in 19 patients. CONCLUSION: Amitriptyline was effective in relieving pain associated with a somatoform pain disorder in the orofacial region. The dose of amitriptyline may need to be as high as that used to treat a major depression.

Adult↗