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PubMed2004

Do adenosine receptors play a role in amitriptyline-induced cardiovascular toxicity in rats?

OBJECTIVE: The aim of the our study was to investigate the role of adenosine receptors on cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant agent. Therefore, the hypothesis of this study was that adenosine receptor antagonists would improve and/or prevent amitriptyline-induced hypotension and conduction abnormalities in an anesthetized rat model of amitriptyline intoxication. METHODS: Two separate experimental protocols were performed. Amitriptyline intoxication was induced by the infusion of amitriptyline 0.94 mg/kg/min until 40-45% reduction of mean arterial pressure (MAP). Sodium cromoglycate (10 mg/kg) was injected i.v. to inhibit the A3 receptor-mediated activation of mast cells. In protocol 1, after amitriptyline infusion, while control animals (n=8) were given dextrose solution, treatment groups received a selective adenosine A1 antagonist DPCPX (8-cyclopentyl-1,3-Dipropylxanthine, 20 microg/kg/min, n=8) or a selective A2a antagonist CSC (8-(3-chlorostyryl) caffeine, 24 microg/kg/min, n=8) for 60 minutes. In protocol 2, after the sodium cromoglycate, while control group of rats (n=8) recevied a dextrose solution, treatment groups of rats were administered DPCPX (20 microg/kg/min, n=8) or CSC (24 microg/kg/min, n=8) infusion to block adenosine A1 and A2a receptors for 20 minutes before amitriptyline infusion. After pretreatment with adenosine antagonists, all rats were given a dose of 0.94 mg/kg/min of amitriptyline infusion during 60 minutes. Outcome measures were mean arterial pressure (MAP), heart rate (HR), QRS duration and survival rate. RESULTS: In protocol 1, amitriptyline infusion significantly reduced MAP and prolonged QRS within 15 minutes. HR was not changed significantly during the experiments. While dextrose did not improve MAP and QRS prolongation, DPCPX or CSC administration developed a significant improvement in MAP compared to the dextrose group within 10 min (88.5 +/- 2.8%, 75.6 +/- 4.7% and 50.1 +/- 14.7%, p<0.01, p<0.05, respectively). Both DPCPX and CSC decreased QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.00001). In protocol 2, pretreatment with DPCPX or CSC prevented the reduction in MAP due to amitriptyline toxicity compared to rats administered dextrose infusion (99.5 +/- 2.6%, 102.4 +/- 2.6%, 81.8 +/- 5.4, p<0.01 at 30 min; 98.0 +/- 2.9%, 93.5 +/- 6.0%, 64.9 +/- 4.7, p<0.001, p<0.01 at 40 min, respectively). Pretreatment with DPCPX or CSC also prevented the QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.0001). CONCLUSION: Adenosine antagonists were found to be effective in improving hypotension, QRS prolongation and survival time in our rat model of amitriptyline toxicity. Additionally, amitriptyline-induced cardiotoxicity was abolished by pretreatment with adenosine receptor antagonists. These results suggest that adenosine receptors may have a role in the pathophysiology of amitriptyline-induced cardiovascular toxicity. Adenosine A1 and A2a receptor antagonists may be promising agents for reversing amitriptyline-induced cardiovascular toxicity.

Amitriptyline↗
PubMed2003

Amitriptyline versus other types of pharmacotherapy for depression.

BACKGROUND: For many years amitriptyline has been considered one of the reference compounds for the pharmacological treatment of depression. However, new tricyclic drugs, heterocyclic compounds and the selective serotonin reuptake inhibitors have been introduced on the market with the claim of a more favourable tolerability/efficacy profile. OBJECTIVES: The aim of the present systematic review was to investigate the tolerability and efficacy of amitriptyline in comparison with the other tricyclic/heterocyclic antidepressants and with the selective serotonin reuptake inhibitors. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (2002-3) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Key journals and conference abstracts were handsearched. Pharmaceutical companies were contacted for information on unpublished materials. SELECTION CRITERIA: Only randomised controlled trials were included. Study participants were of either sex and any age with a primary diagnosis of depression. Included trials compared amitriptyline with another tricyclic/heterocyclic antidepressant or with one of the selective serotonin reuptake inhibitors. DATA COLLECTION AND ANALYSIS: Data were extracted using a standardised form. The number of patients undergoing the randomisation procedure, the number of patients who completed the study and the number of improved patients were extracted. In addition, group mean scores at the end of the trial on Hamilton Depression Scale or any other depression scale were extracted. In the tolerability analysis, the number of patients failing to complete the study and the number of patients complaining of side-effects was extracted. MAIN RESULTS: The estimate of the overall odds ratio for responders showed that more subjects responded to amitriptyline in comparison with the control antidepressant group (odds ratio 1.12, 95% confidence interval 1.01, 1.23, number needed to treat 50). The estimate of the efficacy of amitriptyline and control agents on a continuous outcome revealed an effect size which also significantly favoured amitriptyline (Standardised Mean Difference 0.13, 95% confidence interval 0.04, 0.23). Whilst these differences are statistically significant, their clinical significance is less clear. When the efficacy analysis was stratified by drug class, no difference in outcome emerged between amitriptyline and either tricyclic or selective serotonin reuptake inhibitor comparators. The dropout rate in patients taking amitriptyline and control agents was similar; however, the estimate of the proportion of patients who experienced side-effects significantly favoured control agents in comparison with amitriptyline (odds ratio 0.63, 95% confidence interval 0.56, 0.71). When the tolerability analysis was stratified by drug class, the dropout rate in patients taking amitriptyline and the selective serotonin reuptake inhibitors significantly favoured the latter (odds ratio 0.84, 95% confidence interval 0.75,0.95, number needed to harm 40). When the responder analysis was stratified by study setting amitriptyline was more effective than control ADs in inpatients (odds ratio 1.22, 95% confidence interval 1.04, 1.42, number needed to treat 24), but not in outpatients (odds ratio 1.01, 95% confidence interval 0.88, 1.17, number needed to treat = 200). REVIEWER'S CONCLUSIONS: This present systematic review indicates that amitriptyline is at least as efficacious as other tricyclics or newer compounds. However, the burden of side-effects in patients receiving it was greater. In comparison with the selective serotonin reuptake inhibitors amitriptyline was less well tolerated, and although counterbalanced by a higher proportion of responders, the difference was not statistically significant.

Amitriptyline↗
PubMed1991

Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites.

Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 microM) and diphenylhydantoin (10-80 microM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17 degrees C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (tau r) from block by amitriptyline at -130 mV was very slow (13.6 +/- 3.2 seconds), whereas tau r during diphenylhydantoin exposure was fast (0.71 +/- 0.21 seconds, p less than 0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, tau r was found to be 6.6 +/- 1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pHo revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo was increased from 7.4 to 8.0, tau r was reduced approximately threefold (from 13.6 +/- 3.2 to 4.2 +/- 0.1 seconds, p less than 0.0001) during exposure to amitriptyline, but no effect was seen on tau r after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, tau r after amitriptyline was unaffected, but tau r after diphenylhydantoin markedly increased (from 0.71 +/- 0.21 to 2.60 +/- 1.30 seconds, p less than 0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of -130 to -90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data.(ABSTRACT TRUNCATED AT 400 WORDS)

Amitriptyline↗
PubMedDate not supplied

Neurologic and histopathologic evaluation after high-volume intrathecal amitriptyline.

BACKGROUND AND OBJECTIVES: Accumulating evidence indicates that amitriptyline decreases pain sensation when administered orally, intraperitoneally, or for sciatic nerve block. Previous reports of intrathecal administration of amitriptyline have yielded inconsistent results. The failure of amitriptyline to provide antinociception may partly be related to its high logP (octanol-water partition coefficient) and consequent poor spread within the cerebrospinal fluid. We evaluated spinal block after various concentrations of amitriptyline administered intrathecally in a fixed high volume. METHODS: We administered 100 microL of 5, 10, 15.9 (0.5%), 25, 50, or 100 mmol/L amitriptyline hydrochloride solution or 100 microL of 15.4 mmol/L (0.5%) bupivacaine hydrochloride solution intrathecally to rats. The neurologic deficit was evaluated by antinociceptive, motor, and proprioceptive responses, and the spinal cord was examined for histopathologic changes. RESULTS: Doses of 100 microL amitriptyline at 15.9 mmol/L (0.5%) and 25 mmol/L produced longer complete nerve block than did bupivacaine at 15.4 mmol/L (0.5%); 5 and 10 mmol/L amitriptyline produced only partial nerve block. However, with 100 microL intrathecal amitriptyline at 50 and 100 mmol/L, many rats did not fully recover from spinal block. Severe axonal degeneration, myelin breakdown, and replacement of neuronal structures by vacuoles were seen in the spinal root section of animals injected with concentrations higher than 25 mmol/L amitriptyline. CONCLUSIONS: At lower doses, intrathecal injection of high volumes of amitriptyline results in long-acting spinal block. At higher doses, intrathecal amitriptyline results in irreversible neurologic deficit. Therefore, we do not recommend the use of intrathecal amitriptyline because of a very low therapeutic index.

Amitriptyline↗
PubMed1997

A physiologic assessment of intrathecal amitriptyline in sheep.

BACKGROUND: Intrathecal injection of amitriptyline enhances antinociception from intravenous morphine and reduces neuropathic pain behavior in animals. This study represents part of a preclinical assessment of intrathecal amitriptyline to determine its safety for use in humans. METHODS: Low thoracic intrathecal, femoral, and pulmonary arterial catheters were inserted in 18 adult ewes, followed 96 h later by intrathecal injection of saline or 5 mg amitriptyline and by determination of spinal cord blood flow, hemodynamic variables, behavioral changes, cerebrospinal fluid concentrations of catecholamines and amitriptyline, and spinal tissue concentrations of amitriptyline. In six other ewes, low thoracic intrathecal and femoral arterial catheters were inserted and blood pressure and heart rate were measured after intrathecal injection of saline or 0.25, 1, or 5 mg amitriptyline. Four other ewes received cervical intrathecal injection of 5 and 10 mg amitriptyline, and antinociception was determined. RESULTS: Thoracic intrathecal injection of amitriptyline produced dose-dependent sedation but did not significantly affect spinal cord blood flow or hemodynamic variables. Spinal cord tissue concentrations of amitriptyline were 100 times greater in tissue near the tip of the thoracic intrathecal catheter compared with cervical cord tissue. Cerebrospinal fluid concentrations of catecholamines did not significantly change after amitriptyline was administered. Cervical intrathecal injection of 5 mg amitriptyline produced mild antinociception, whereas 10 mg produced intense sedation and, in one sheep, seizures and death. CONCLUSIONS: Although other preclinical toxicity studies are necessary before introducing intrathecal amitriptyline for use in humans, this study did not reveal dangerous changes in blood pressure or spinal cord blood flow from this agent.

Amitriptyline↗
PubMed1989

Cardiovascular (ECG and systolic time intervals) and anticholinergic effects of repeated doses of femoxetine--a comparison with amitriptyline and placebo in healthy men.

1. The cardiovascular and anticholinergic effects of femoxetine and amitriptyline were compared with those of placebo in a double-blind cross-over trial in 12 healthy men. The daily doses administered were therapeutic: 600 mg femoxetine and 150 mg amitriptyline. Duration of treatment with each drug was 13 days. 2. The statistically significant effects on systolic time intervals and ECG comprised a larger decrease of QS2 index during femoxetine than during amitriptyline, and an increase of PEP/LVET ratio and QRS duration by amitriptyline. These results suggest that femoxetine and, to a lesser extent, amitriptyline increase contractility compared with placebo, and amitriptyline, but not femoxetine, causes delay in intracardiac conduction. 3. The effects of amitriptyline on the systolic time intervals are difficult to interpret because of the changes in heart rate and intracardiac electrical conduction caused by the drug. These problems of interpretation are discussed. 4. No significant changes in blood pressure were observed. The heart rate during both femoxetine and amitriptyline periods was significantly faster than during the placebo period, amitriptyline causing a significantly greater increase. 5. Salivary secretion was decreased more by amitriptyline (26%) than by femoxetine (8%), the latter being not significantly different from placebo. Femoxetine tended to increase pupil diameter and amitriptyline to increase accommodation near point, but no visual disturbances were reported on any treatment. Symptoms such as dry mouth, constipation and sedation were significantly less frequently reported during femoxetine than during amitriptyline treatment.

Administration, Oral↗
PubMed1998

Differential inhibition of catecholamine secretion by amitriptyline through blockage of nicotinic receptors, sodium channels, and calcium channels in bovine adrenal chromaffin cells.

We investigated the effects of amitriptyline, a tricyclic antidepressant, on [3H]norepinephrine ([3H]NE) secretion and ion flux in bovine adrenal chromaffin cells. Amitriptyline inhibited [3H]NE secretion induced by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and 70 mM K+. The half maximal inhibitory concentration (IC50) was 2 microM and 9 microM, respectively. Amitriptyline also inhibited the elevation of cytosolic calcium ([Ca2+]i) induced by DMPP and 70 mM K+ with IC50 values of 1.1 microM and 35 microM, respectively. The rises in cytosolic sodium ([Na+]i) and [Ca2+]i induced by the Na+ channel activator veratridine were also inhibited by amitriptyline with IC50 values of 7 microM and 30 microM, respectively. These results suggest that amitriptyline at micromolar concentrations inhibits both voltage-sensitive calcium (VSCCs) and sodium channels (VSSCs). Furthermore, submicromolar concentrations of amitriptyline significantly inhibited DMPP-induced [3H]NE secretion and [Ca2+]i rise, but not veratridine- or 70 mM K+-induced responses, suggesting that nicotinic acetylcholine receptors (nAChR) as well as VSCCs and VSSCs can be targeted by amitriptyline. DMPP-induced [Na+]i rise was much more sensitive to amitriptyline than the veratridine-induced rise, suggesting that the influx of Na+ and Ca2+, through the nAChR itself is blocked by amitriptyline. Receptor binding competition analysis showed that binding of [3H]nicotine to chromaffin cells was significantly affected by amitriptyline at submicromolar concentrations. The data suggest that amitriptyline inhibits catecholamine secretion by blocking nAChR, VSSC, and VSCC.

Adrenal Glands↗
PubMed1977

Quantitative determination of amitriptyline and its principal metabolite, nortriptyline, by GLC-chemical ionization mass spectrometry.

A quantitative GLC-mass spectrometry assay was developed for the determination of the tricyclic antidepressant amitriptyline and its desmethyl metabolite (nortriptyline) in human plasma. The assay utilizes selective ion detection to monitor in a GLC effluent the MH+ molecular ions of amitriptyline and nortriptyline generated by isobutane chemical ionization. The procedure, which utilizes deuterated analogs of amitriptyline and nortriptyline as internal standards, requires 1 ml of plasma and can measure 1 ng/ml of amitriptyline and 0.5 ng/ml of nortriptyline. The curves relating the amounts of amitriptyline and nortriptyline added versus the amounts found over a 100-fold range of amitriptyline and nortriptyline concentrations are straight lines with intercepts of approximately zero and slopes of unity. Analyses of plasma samples from three subjects receiving 50 mg of amitriptyline orally, three times a day, gave an average plasma concentration of 115 +/- 42 ng/ml for amitriptyline and 109 +/- 20 ng/ml for nortriptyline. Similar analyses of the plasma of three subjects who had received a single 50-mg oral dose of amitriptyline showed an average maximum plasma concentration of 25 +/- 10 ng/ml for amitriptyline and 10 +/- 4 ng/ml for nortriptyline. Seventy-two hours after adminis-ration, the average plasma amitriptyline and nortriptyline levels were 3 +/- 2 ng/ml, respectively.

Adult↗
PubMed1999

Pharmacokinetic and pharmacodynamic characterization of OROS and immediate-release amitriptyline.

AIMS: To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS and IR treatments, and to correlate them with anticholinergic side-effects. METHODS: The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS tablet, three 25 mg IR tablets administered every 8 h, or 3x25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period. RESULTS: Following dosing with OROS (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml-1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml-1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration. CONCLUSIONS: The bioavailability of OROS (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.

Adult↗
PubMed2001

Amitriptyline versus bupivacaine in rat sciatic nerve blockade.

BACKGROUND: Amitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of amitriptyline in rats and in vitro. METHODS: Sciatic nerve blockade was performed with 0.2 ml amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated. RESULTS: Complete sciatic nerve blockade for nociception was obtained with amitriptyline for 217 +/- 19 min (5 mM, n = 8, mean +/- SEM) and for 454 +/- 38 min (10 mM, n = 7) versus bupivacaine for 90 +/- 13 min (15.4 mM, n = 6). The time to full recovery of nociception for amitriptyline was 353 +/- 12 min (5 mM) and 656 +/- 27 min (10 mM) versus 155 +/- 9 min for bupivacaine (15.4 mM). Amitriptyline was approximately 4.7-10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 +/- 2.7 vs. 189.6 +/- 22.3 microM) at - 150 mV, and to the inactivated Na+ channels (IC50 of 0.9 +/- 0.1 vs. 9.6 +/- 0.9 microM) at -60 mV. High-frequency stimulation at 3 microM caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for amitriptyline. CONCLUSION: Amitriptyline is a more potent blocker of neuronal Na+ channels than bupivacaine in vivo and in vitro. These findings suggest that amitriptyline could extend its clinical usefulness for peripheral nerve blockade.

Amitriptyline↗
PubMed2003

Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes.

BACKGROUND: Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. METHODS: The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). RESULTS: In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. CONCLUSIONS: Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

Amitriptyline↗
PubMed1997

A comparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics.

OBJECTIVE: To compare amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. DESIGN: A double-blind, crossover trial of treatment with amitriptyline, maprotiline, and placebo. Treatment was given in randomized order for periods of 4 weeks. Each period was separated by a 1-week washout. The final dose was 75 mg/day for both amitriptyline and maprotiline. PATIENTS: Thirty-seven patients with diabetic and nondiabetic painful polyneuropathy. OUTCOME MEASURES: The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale (0 = no pain and 10 = worst thinkable pain) and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale (pain relief scale). For the assessment of depression, the Comprehensive Psychopathological Rating Scale (CPRS) was used. RESULTS: Using the global assessment of pain relief at the end of each treatment period, 22 of 33 patients reported reduced pain on amitriptyline treatment compared with 14 of 33 patients on maprotiline treatment and 8 patients on placebo treatment (p < .0001 and p < .05 for amitriptyline and maprotiline, respectively, against placebo). Amitriptyline was slightly better than maprotiline (p < .05) [tested by repeated measures analysis of variance (ANOVA)]. The order in which treatments occurred and the diagnosis of diabetes or nondiabetes did not have any significant effect on the global rating of pain relief. The mean values of the daily ratings of pain intensity showed that pain was more severe in the evenings than in the mornings and that diabetic patients reported worse pain than nondiabetics at baseline. The mean values of pain reduction as assessed with the 10-step verbal scale during the 4th week of treatment showed that amitriptyline and maprotiline were significantly better than placebo in relieving the pain (p < .0001 and p < .01, respectively, post hoc test according to Scheffé). However, there was no significant difference between the pain reduction of amitriptyline compared with maprotiline when assessing pain reduction with the 10-step verbal scale during the 4th treatment week. Nor was there a significant difference between diabetics and nondiabetics with regard to the effect of the drugs. The clinical effect was not significantly correlated to plasma concentration of either amitriptyline and its active metabolite nortriptyline or maprotiline in the global or daily assessments. The effect of treatment was not correlated to any particular pain quality nor to the intensity of pain. Depression was noted in three patients who completed the medication trial, but the effect of treatment of pain and depression did not clearly correlate. The adverse side effects of amitriptyline and maprotiline were common, and in 5 patients the medication had to be discontinued because of severe side effects. CONCLUSION: From the present results and the literature, it is concluded that tricyclic antidepressants with a pharmacologic profile similar to amitriptyline are the most effective drugs in the treatment of polyneuropathy pain in both diabetic and nondiabetic patients.

Adult↗