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PubMed1993

Low-dose amitriptyline as an adjunct to opioids for postoperative orthopedic pain: a placebo-controlled trial.

Tricyclic antidepressants (TCAs) have been found to be useful in the management of a variety of chronic pain conditions, although there is little published regarding the potential efficacy of this class of drug as an adjunct for the control of acute postoperative pain and related symptoms. Twenty-eight patients undergoing total hip or knee arthroplasty completed a randomized, placebo-controlled, double-blinded trial of 50 mg of amitriptyline p.o. HS on postoperative days 1, 2 and 3 while using patient-controlled morphine or meperidine analgesia (PCA). Visual analog (VAS) and numerical verbal (NVS) pain ratings, sedation scores, sleep quantity/quality scores, and sense of well-being scores were assessed twice daily on each of the days succeeding amitriptyline/placebo use. Hourly opioid use was recorded and transcribed from the memory of the PCA devices in use. Mean scores in the amitriptyline group for pain NVS were greater (P < 0.05) (higher score = greater pain) on day 1 and greater on day 2 for the pain VAS. Mean scores for sense of well-being were greater (P < 0.05) (higher score = better sense of well-being) for the placebo group on days 1 and 2. On days 2 and 3, sleep scale variable mean scores were worse in the placebo group (P < 0.025). There were no other statistically significant differences between the control and active drug groups for any of the outcome variables measured. We conclude that amitriptyline at the dose prescribed is no different than placebo in altering the majority of postoperative symptom variables studied in the sample study population but caused no significant adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Effects of amitriptyline and nortriptyline on cerebral activity of the CDF-1 mouse strain.

1. Equal dose regimens of amitriptyline, a tertiary amine tricyclic antidepressant, were more potent than nortriptyline, a secondary amine derivative, in suppressing CDF-1 mouse locomotor activity. 2. A suggestive increase in dopamine turnover rate in mouse cerebral cortex and striatal brain regions was apparent by amitriptyline but not nortriptyline. 3. A suggestive increase in serotonin turnover in mouse cerebellum and striatum was determined for nortriptyline. 4. Both antidepressants increased cerebral cortex, midbrain and cerebellum serotonin levels from saline control. 5. Increases of regional brain dopamine by amitriptyline and serotonin by nortriptyline concurrent with reuptake blockade of the respective serotonin and dopamine may contribute to their differential extrapyramidal and sedating side effects.

Amitriptyline↗

PubMed1979

Metabolic interaction between amitriptyline and perphenazine in psychiatric patients.

1. Steady-state plasma level samples of sixty-five schizophrenic patients from two psychiatric hospitals assigned to three treatment groups (amitriptyline 150 mg/day, perphenazine 20 mg/day and a combination of amitriptyline and perphenazine at 150 mg and 20 mg/day) were assayed for amitriptyline (AT), endogenous nortriptyline (NT) and perphenazine (PPZ) using gas-liquid chromatography. 2. Results reveal that AT and NT levels are independent of sex and hospital environment. 3. PPZ significantly increased the steady-state NT plasma levels, probably through inhibition of the hydroxylation biotransformation pathway, but had no effect on AT levels, thus indicating that PPZ has no influence on the desmethylation pathway, or alternatively, the hydroxylation of AT.

Adult↗

PubMed1979

Pharmacokinetics and pharmacodynamics of amitriptyline in depression.

1. The therapeutic effect and pharmacokinetics of amitriptyline were assessed in thirty-five patients suffering from primary depressive illness during inpatient treatment. 2. Contrary to our previous study, no significant correlation was obtained between the plasma concentrations of amitriptyline, nortriptyline or total tricyclics with Hamilton rating score at 6 weeks or percentage improvement after 6 weeks treatment. 3. There was also no correlation with the plasma concentrations of tricyclics with the corrected subjective side-effects score. 4. A linear correlation (rs = 0.80; p less than 0.001) was observed between the plasma concentration of nortriptyline and decreased tyramine sensitivity, an index of noradrenaline reuptake blocking effect. 5. The corrected side-effect score during the trial correlated (r = 0.64; p less than 0.001) with Hamilton rating score at week 6, i.e. the patients who complained of more side-effects had less clinical benefit during amitriptyline therapy.

Amitriptyline↗

PubMed1996

Simultaneous determination of amitriptyline, nortriptyline and four hydroxylated metabolites in serum by capillary gas-liquid chromatography with nitrogen-phosphorus-selective detection.

A method for the simultaneous quantification of the antidepressant drug amitriptyline, its demethylated metabolite nortriptyline and four hydroxy metabolites (E-10-hydroxyamitriptyline, Z-10-hydroxyamitriptyline, E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline) in human serum or plasma has been developed. The method is based on a three-step liquid-liquid extraction followed by gas-liquid chromatography (split-splitless injection, HP-5, 25 m x 0.2 mm I.D., 0.33 microns capillary) with nitrogen-phosphorus-selective detection (GLC-NPD). The limits of detection are 1.5 ng/ml for amitriptyline, nortriptyline, E-10-hydroxyamitriptyline and Z-10-hydroxyamitriptyline and 3 ng/ml for E-10-hydroxynortiptyline and Z-10-hydroxynortriptyline. The within-day and between-day precision is between 6 and 15% at three concentrations (low, moderate and high) for amitriptyline, nortriptyline and E-10-hydroxy metabolites. At low concentrations of 10 ng/ml, the precision of the assay of the Z-10-hydroxy metabolites has been found to be up to 19%. Accuracy is between 91 and 115% for all analytes. The performance of the assay of the hydroxy metabolites is mainly determined by the cleanness and the deactivation of the quartz insert of the injector port. Therefore, every day a freshly cleaned and deactivated insert was used.

Amitriptyline↗

PubMed1987

Correlation of initial amitriptyline concentration reduction with activated charcoal therapy in overdose patients.

Plasma amitriptyline concentrations were measured serially in nine overdose patients and correlated with the timing and amount of each patient's initial activated charcoal therapy. A direct correlation was found between the time to initial charcoal therapy (Tc) and the plasma concentration half-life of amitriptyline (T 1/2) calculated for the first seven to 18 hours of hospitalization; T 1/2 = 2.68 + 0.047 Tc (r = 0.78, P less than 0.05). An inverse trend of T 1/2 with the initial amount of charcoal administered was also noted. Nortriptyline, the major metabolite of amitriptyline, decreased in two of three patients who received greater than or equal to 50 gm of activated charcoal within 60 minutes of presentation. These findings support previous in vitro and human volunteer studies advocating the rapid administration of activated charcoal in acute tricyclic antidepressant overdoses.

Amitriptyline↗

PubMed2006

Sequestration of amitriptyline by liposomes.

We study the uptake of amitriptyline, which is a common cause of overdose-related fatalities, in aqueous solutions by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes and liposomes composed of a mixture of DMPC and 1,2-dioleoyl-sn-glycero-3-[phospho-rac(1-glycerol)] (DOPG) lipids. The effect of drug concentration, liposomal charge, pH, salt, and protein presence on the drug uptake is investigated using two different methodologies, a precipitation and a centrifugation method. Furthermore, the time scale of the drug uptake is studied through qualitative observations at high pH and through conductivity measurements at neutral pH and found to be <5 s. The results of the quantitative studies show that the fractional drug uptake decreases with increasing drug concentration, and for a given concentration it increases with the pH and decreases in the presence of salt. We find that a larger amount of drug is sequestered by negatively charged liposomes (those containing DOPG) than liposomes with no net charge (DMPC). We speculate that the mechanism of drug uptake is due to both electrostatic interactions as well as hydrophobic effects. The fractional uptake by DMPC:DOPG in a 70:30 ratio is as high as 95% in water and about 90% in physiological buffer. The fractional uptake is also measured in presence of 2% (w/w) bovine serum albumin (BSA), which is approximately the protein concentration in the intercellular fluid. In presence of protein the fractional uptakes by 70:30 DMPC:DOPG liposomes and 50:50 DMPC:DOPG liposomes are 82 and 90%, respectively, at 125 muM drug amitriptyline. In the absence of liposomes, 67% of the drug is taken up by the protein in a 2% (w/w) BSA, 125 muM amitriptyline solution. Thus, addition of 50:50 DMPC:DOPG liposomes reduces the free drug concentration by a factor of about 3.5, making them attractive candidates for drug detoxification.

Amitriptyline↗

PubMed2005

Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study.

UNLABELLED: Twenty eight subjects with refractory, moderate to severe peripheral neuropathic pain participated in an open label prospective trial examining perceived analgesic effect, patient satisfaction, and safety of topical amitriptyline 2%/ketamine 1% cream. Outcome measures included an 11-point numerical rating scale for pain intensity (NRS-PI), a 5-point satisfaction scale, blood chemistry screen, drug and metabolite levels, urinalyses, electrocardiogram (ECG), and physical examination. Adverse events were monitored. Twenty-one subjects completed the trial. At 6 months, subjects reported an average long-term reduction in pain of 34% (standard deviation [SD] = 37%); 5 subjects (25%) achieved 50% or greater reduction in pain and 1 subject (5%) achieved 100% reduction in pain. At 12 months, the average reduction in pain was 37% (SD = 40%); 7 subjects (40%) achieved 50% or greater pain reduction. At the end of the study, 89% of subjects rated their satisfaction as 3/5 or greater and 2 subjects (10%) were pain free. Minimal adverse events were reported and there were no serious medication related adverse events. Blood levels revealed minimal systemic absorption. In conclusion, topical 2% amitriptyline/ 1% ketamine cream was associated with long-term reduction (6-12 months) in perceived pain, moderate to complete satisfaction, and was well tolerated in treatment of neuropathic pain. There was no significant systemic absorption of amitriptyline or ketamine. PERSPECTIVE: This study demonstrates that topical 2% amitriptyline/1% ketamine, given over 6-12 months, is associated with long-term perceived analgesic effectiveness in treatment of neuropathic pain. Antidepressants and ketamine both produce multiple pharmacologic effects that may contribute to peripheral analgesia; such actions include block of peripheral N-methyl-D-aspartate receptors, local anesthetic properties, and interactions with adenosine systems.

Adenosine↗

PubMed2004

Peripherally administered amitriptyline derivatives have differential anti-allodynic effects in a rat model of neuropathic pain.

We assessed if derivatives of amitriptyline could alleviate mechanical allodynia in a rat model of neuropathic pain. N-methyl amitriptyline (NMA), and amitriptyline HCl (AHC) were compared to evaluate the antiallodynic effects produced by systemic and peripheral administration. Under general anesthesia with halothane, neuropathic injury was produced in rats by tightly ligating the left L5 and L6 spinal nerves. All animals developed neuropathic pain behaviors within 7 days after the surgery. For systemic delivery, three groups of rats were injected intraperitoneally with NMA (15 mg/kg), AHC (12.5 mg/kg), or saline. For peripheral routes of injection, rats were divided into 3 x 3 groups and injected with 100, 330, and 1000 nmol/kg doses of each NMA, AHC and 0.9% normal saline. NMA and AHC suppressed mechanical allodynia following peripheral administration but not following intraperitoneal injection. NMA was less potent but showed a longer-acting response than AHC. This study shows that NMA can be used to relieve mechanical allodynia and is a longer-acting agent than AHC.

Amitriptyline↗

PubMed1999

Amitriptyline increases GABA-stimulated 36Cl- influx by recombinant (alpha 1 gamma 2) GABAA receptors.

WSS-1 cells expressing (alpha 1 gamma 2)GABAA receptors show an augmented 36Cl- response to GABA in the presence of amitriptyline that is increased by flumazenil, unlike augmentation by diazepam which is blocked by flumazenil. This amitriptyline effect is opposite to the inhibition of GABA-stimulated 36Cl influx manifested in membrane vesicles prepared from drug-naive rats or submissive rats (a model of depression) but is similar to that seen in tissue from amitriptyline-treated rats or dominant rats. The results suggest a novel mechanism of antidepressant drug action having a delayed onset.

Amitriptyline↗

PubMed1982

Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?

Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.

Adult↗

PubMed2002

A comparison of characteristics of depressed patients and efficacy of sertraline and amitriptyline between Japan and the West.

BACKGROUND: This study was conducted to investigate the differences and similarities of the profile of depressed patients and the efficacy of the antidepressants, sertraline and amitriptyline, between Japan and the West (United States, Europe), using the Hamilton Depression Rating Scale (HAM-D) score of the individual patients. METHODS: Using common selection criteria, 680 patients from three regional clinical studies were chosen for this investigation. Factor analysis of the HAM-D scores for each regional group was carried out to compare the profile of depressed patients. Analysis of covariance was used to compare the efficacy of sertraline and amitriptyline between the regions. RESULTS: Factor analyses clearly showed three main factors (major depressive symptoms, anxiety and sleep disturbance) to be common across all three geographic regions. Higher HAM-D component scores of "Work and interests" and "Retardation" and lower ones of "Depressed mood" and "Feeling of guilt" were observed for the Japanese patients compared to the Western patients. Improvement of anxiety symptoms was marked for the Japanese amitriptyline treated patients. LIMITATIONS: Although the patient data used in these analyses were restricted by using identical selection criteria, there still remains some methodological shortcomings due to the original study design differences. CONCLUSIONS: Overall, the three main factors of depression and their magnitudes were similar between Japan and the West. The presentation of major depressive symptoms in Japanese patients differed from Western patients; this could be related to social, cultural and religious differences. Marked sedative effect for Japanese patients appeared to be due to the factor of anxiety being the strongest of the three main factors in Japanese depressed patients.

Adult↗

PubMed1999

Serotonin receptor subtype gene expression in the hippocampus of aged rats following chronic amitriptyline treatment.

The raphe-hippocampal 5-HT system plays a key role in the modulation of mood, memory and neuroendocrine responses. In the elderly, there is an increased incidence of disturbances of these functions. We examined the effects of ageing and of chronic antidepressant treatment upon 5-HT receptor subtype mRNA expression in the hippocampus and raphe of cognitively tested rats. Amitriptyline treatment decreased 5-HT1A receptor mRNA expression in the dorsal raphe nucleus of the aged rats (24% fall compared to saline treated controls, p<0.01) but not in the young rats. Neither age nor amitriptyline (10 mg/kg, i.p.) administration for 10 weeks altered 5-HT1A, 5-HT2A, 5-HT2C or 5-HT7 receptor mRNA expression in any hippocampal subregion. This suggests a difference in responsiveness to amitriptyline with ageing originating at the level of the raphe 5-HT1A autoreceptor gene expression.

Aging↗

PubMed1995

Does a sodium-free buffer affect QRS width in experimental amitriptyline overdose?

STUDY OBJECTIVES: We carried out this study to determine the effects of pH alteration on QRS width with administration of tromethamine, a non-sodium-containing buffering agent, in experimental amitriptyline overdose. DESIGN: Prospective, nonblinded trial. PARTICIPANTS: Adult mongrel dogs. INTERVENTIONS: Pentobarbital-anesthetized dogs were overdosed with amitriptyline 5 mg/kg followed by infusion at 1.0 mg/kg/minute until the QRS width doubled, then decreased to .5 mg/kg/minute until the end of the experiment. At two defined points of toxicity, the dose of tromethamine required to raise the pH to 7.50 +/- 4 was given. pH and QRS width at a speed of 100 mm/second were measured over a 30-minute period after each tromethamine dose. Data were analyzed with non-linear-regression analysis. RESULTS: At toxicity 1 the mean pH was 7.32, with a QRS width of 11.6 mm. Two minutes after the tromethamine dose the pH rose to 7.51, with narrowing of the QRS width to 8.4 mm. At toxicity 2 the pH was 7.40, with QRS width of 10.6 mm. Two minutes after tromethamine, the pH rose to 7.49 and the QRS width decreased to 9.7 mm. Regression analysis showed a correlation between pH and QRS width; as pH increased, QRS width decreased (P = .0001). CONCLUSION: Cardiac toxicity of amitriptyline overdose, as manifested by QRS widening, is reversible by pH changes alone.

Amitriptyline↗

PubMed1999

Chronic amitriptyline administration increases serotonin transporter binding sites in the hippocampus of aged rats.

The effects of ageing and of chronic antidepressant treatment upon 5-HT transporter sites ([3H]paroxetine binding) in the rat hippocampus was examined. [3H]paroxetine binding to transporter sites was decreased with ageing in the hippocampus of control rats (38% decrease in dentate gyrus and CA4). Amitriptyline (10 mg/kg, i.p.) had no significant effect on [3H]paroxetine binding in 10 months old rats, but increased binding sites in 24 months rats in all hippocampal subregions (greatest increase of 109% in CA1 compared to saline controls). These data indicate an age-related decrease in hippocampal serotonin transporter sites and upregulation of these sites following 10 weeks of amitriptyline. The observed increase in transporter sites following amitriptyline may contribute to the general lower effectiveness of tricyclic antidepressants with ageing.

Aging↗

PubMed2002

Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial.

Chronic pain in persons with spinal cord injury (SCI) is a difficult problem for which there is no simple method of treatment. Few randomized controlled trials of medications for pain in persons with SCI have been conducted. This study was designed to determine whether amitriptyline, a tricyclic antidepressant, is efficacious in relieving chronic pain and improving pain-related physical and psychosocial dysfunction in persons with SCI. Eighty-four participants with SCI and chronic pain were randomized to a 6-week trial of amitriptyline or an active placebo, benztropine mesylate. All pre- and post-treatment assessments were conducted by evaluators blind to the allocation. Regression analyses were conducted to examine whether there was a medication group effect on the primary (average pain intensity) and secondary outcome measures. No significant differences were found between the groups in pain intensity or pain-related disability post-treatment, in either intent-to-treat analyses or analyses of study completers. These findings do not support the use of amitriptyline in the treatment of chronic pain in this population, but we cannot rule out the possibility that certain subgroups may benefit.

Adult↗

PubMed1983

Quantification of amitriptyline, nortriptyline, and 10-hydroxy metabolite isomers in plasma by capillary gas chromatography with nitrogen-sensitive detection.

A selective, sensitive method for the determination of amitriptyline and its metabolites is described. This method involves liquid-liquid extraction and capillary gas chromatography with nitrogen-sensitive detection. The detection limits of amitriptyline, nortriptyline, 10-hydroxy(E)amitriptyline, 10-hydroxy(E)nortriptyline, and 10-hydroxy(Z)nortriptyline were slightly less than 0.5 ng/ml in 1.0-ml plasma samples. The coefficients of variation for within-run and between-run analyses of samples containing 100 ng/ml were less than 12% and 9%, respectively. The method offers rapid analysis of individual isomers, increased sensitivity over high-performance liquid chromatographic methodology and the conveniences of the gas chromatographic technique.

Amitriptyline↗

PubMed2000

Economic impact of using mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in the UK.

This study modelled the economic impact of mirtazapine, compared to amitriptyline and fluoxetine, in the management of moderate and severe depression in the UK, as well as the costs related to discontinuation of antidepressant treatment. Decision models of the management of moderate and severe depression were developed from clinical trial data, resource use obtained from interviews with general practitioners and psychiatrists, and published literature, and were used to estimate the expected direct National Health Service (NHS) costs of managing a patient with moderate or severe depression. The expected cost of healthcare resource use attributable to managing a patient suffering from moderate or severe depression who discontinues antidepressant treatment, irrespective of the initial treatment, was estimated to be pounds sterling 206 (range pounds sterling 50 to pounds sterling 504) over five months. Using mirtazapine instead of amitriptyline for seven months increases the proportion of successfully treated patients by 21% (from 19.2 to 23.2%) and reduces the expected direct NHS cost by pounds sterling 35 per patient (from pounds sterling 448 to pounds sterling 413). Using mirtazapine instead of fluoxetine for six months increases the proportion of successfully treated patients by 22% (from 15.6 to 19.1%), albeit for an additional cost to the NHS of pounds sterling 27 per patient (from pounds sterling 394 to pounds sterling 420). In conclusion, this study suggests that mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine in the management of moderate and severe depression in the UK.

Adolescent↗