A study on electrocardiographic changes secondary to the use of tricyclic antidepressants in patients with chronic pain

Abstracts

JUSTIFICATIVA E OBJETIVOS: Os antidepressivos tricíclicos (ADT) são amplamente utilizados como analgésicos para lombalgias crônicas e dores neuropáticas. O objetivo deste estudo foi avaliar as alterações eletrocardiográficas dos pacientes com dor crônica em uso de amitriptilina ou imipramina. MÉTODO: Foram estudados 40 pacientes com idade entre 26 e 81 anos (57,27 ± 13,65 anos), de ambos os gêneros (feminino 19, masculino 21), com síndromes neuropáticas (lombociatalgias, síndromes pós-laminectomia, neurites pós-herpética, entre outras); 60% com doenças cardiovasculares; 30% tinham ECG alterado (BRD, BRE, BAV 1º grau, HBAE ou extra-sístoles). Foram realizados e analisados três ECGs: antes do início dos ADT, 30 e 60 dias após o início do tratamento, avaliando os parâmetros PR, QRS, QT, QTc, DQT, DQTc e FC. Trinta e dois pacientes fizeram uso de amitriptilina e oito de imipramina. A dose média ao final do estudo foi de 54,29 mg de amitriptilina e de 46,87 mg de imipramina. RESULTADOS: A análise das variáveis eletrocardiográficas após o uso dos ADT apresentou a amitriptilina com aumento na frequência cardíaca transitoriamente no gênero feminino (p = 0,049) e a duração do QRS nos pacientes com idade igual ou maior que 60 anos e nos cardiopatas na segunda avaliação (p = 0,01). Nos pacientes que receberam amitriptilina, doses de 75 mg, o intervalo QTc foi maior quando comparado com doses de 25 mg (p = 0,0044). O aumento desses parâmetros evidenciou o efeito da amitriptilina sobre a condução cardíaca; no entanto, não houve comprometimento clínico, pois os valores permaneceram dentro dos limites de normalidade (QRS < 110ms e QTc < 470ms). CONCLUSÕES: O uso clínico dos ADT em dores crônicas mostrou-se seguro e eficaz, não apresentando distúrbio da condução cardíaca com repercussão clínica.

DOR, Crônica; DROGAS; EXAMES COMPLEMENTARES

SCIENTIFIC ARTICLE

A study on electrocardiographic changes secondary to the use of tricyclic antidepressants in patients with chronic pain^*

Estudio de las alteraciones electrocardiográficas con el uso de antidepresivos tricíclicos en pacientes con dolor crónico

Ricardo Joaquim da Cunha Jr., M.D.^I; Louis Barrucand, M.D.^II; Nubia Verçosa, M.D.^III

^IMestre em Medicina do Curso de Pós-Graduação em Cirurgia Geral — Setor Anestesiologia — FM/UFRJ; Anestesiologista e Coordenador do Programa de Tratamento da Dor e Cuidados Paliativos do Hospital Universitário Clementino Fraga Filho (HUCFF)

^IIProfessor Titular de Patologia do Departamento de Anatomia Patológica da FM/UFRJ

^IIIProfessora-Associada, Mestre e Doutora em Medicina do Departamento de Cirurgia da FM/UFRJ; Coordenadora da Graduação e Pós-Graduação em Anestesiologia da FM/UFRJ; Responsável pelo Ambulatório de Avaliação Pré-Anestésica do HUCFF/FM/UFRJ; Certificado de Área de Atuação em Dor SBA-AMB

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Tricyclic antidepressants (TCAs) are widely used as analgesics in chronic lumbar pain and neuropathic pain. The objective of this study was to evaluate the electrocardiographic changes in patients with chronic pain treated with amitriptyline or imipramine.

METHODS: Forty patients, ages 26 to 81 years (57.27 ± 13.65 years) of both genders (female 19, male 21), with neuropathic syndromes (lumbosciatalgia, postlaminectomy syndromes, and post-herpetic neuritis, among others) participated in this study; 60% had cardiovascular diseases; 30% had changes in the ECG (RBBB, LBBB, first-degree AVB, LAHB, or PVCs). Three ECGs were done in each patient: one ECG was done before beginning treatment, and 30 and 60 days after beginning treatment evaluating PR, QRS, QT, QTc, DQT, DQTc, and HR. Thirty-two patients were on amitriptyline and eight on imipramine. The mean dose at the end of the study was 54.29 mg of amitriptyline and 46.87 mg of imipramine.

RESULTS: Analysis of electrocardiographic parameters after the use of TCAs showed that amitriptyline caused a transitory increase in heart rate in females (p = 0.049), and the duration of the QRS in patients 60 years or older and patients with cardiopathies (p = 0.01). In patients who received 75 mg of amitriptyline, the QTc interval was greater when compared to that of patients who received 25 mg of the drug (p = 0.0044). The increase in those parameters demonstrated the effects of amitriptyline on cardiac conduction; however, clinical compromise was not seen, since they remained within normal limits (QRS < 110 msec and QTc < 470 msec).

CONCLUSIONS: The chronic use of TACs proved to be safe and effective, and it did not show changes in cardiac conduction with clinical repercussion.

Key Words: COMPLEMENTARY EXAMS: electrocardiogram; DRUGS: tricyclic antidepressants; PAIN, chronic: neuropathic.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Los antidepresivos tricíclicos (ADT) son muy utilizados como analgésicos para lumbalgias crónicas y dolores neuropáticos. El objetivo de este estudio fue evaluar las alteraciones electrocardiográficas de los pacientes con dolor crónico que usan amitriptilina o imipramina.

MÉTODO: Se estudiaron 40 pacientes con edad entre 26 y 81 años (m = 57,27 ± 13,65 años), de los dos sexos (mujeres 19, hombres 21), con síndromes neuropáticos (lumbociatalgias, síndromes pos-laminectomía, neuritis pos-herpética, entre otras); un 60% con enfermedades cardiovasculares; 30% tenían ECG alterado (BRD, BRE, BAV 1°G, HBAE o extra-sístoles). Se realizaron y se analizaron tres ECGs: antes del inicio de los ADT, 30 y 60 días después del inicio del tratamiento, evaluando los parámetros PR, QRS, QT, QTc, DQT, DQTc y FC. Treinta y dos pacientes usaron amitriptilina y ocho imipramina. La dosis promedio al final del estudio fue de 54,29 mg de amitriptilina y de 46,87 mg de imipramina.

RESULTADOS: El análisis de las variables electrocardiográficas después del uso de los ADT arrojó lo siguiente: la amitriptilina aumentó la frecuencia cardíaca transitoriamente en el sexo femenino (p = 0,049) y la duración del QRS en los pacientes con edad igual o superior a los 60 años y en los cardiópatas en la segunda evaluación (p = 0,01). En los pacientes que recibieron amitriptilina, dosis de 75 mg, el intervalo QTc fue mayor cuando se le comparó a las dosis de 25 mg (p = 0,0044). El aumento de esos parámetros mostró el efecto de la amitriptilina sobre la conducción cardíaca, sin embargo, no se registró comprometimiento clínico, pues los valores permanecieron dentro de los límites de la normalidad (QRS < 110ms y QTc < 470ms).

CONCLUSIONES: El uso clínico de los ADT en dolores crónicos, arrojó resultados seguros y eficaces, y no presentó disturbio de la conducción cardíaca con repercusión clínica.

INTRODUCTION

Tricyclic antidepressants (TACs) are used worldwide in psychiatric patients and in the treatment of chronic pain syndromes. In the United Kingdom, a 40% increase in the prescription of those drugs was seen from 1991 to 1996. In the USA, data from 2000 and 2001 demonstrated that those drugs are prescribed more often than serotoninergic drugs ¹. They are indicated in the treatment of neuropathic pain ², fibromyalgia, irritable bowel syndrome, migraines (prophylaxis) and headaches of cervical origin, and in chronic myofascial pain. Those syndromes are common in patients treated in pain clinics and are difficult to treat, even in state-of-the art centers requiring, frequently, a pharmacological and non-pharmacological approach by the multidisciplinary team.

The main side effects of TACs include: dry mouth, constipation, somnolence, weight gain, mental confusion, urinary retention, postural hypotension, and cardiac arrhythmias. Some authors, based on studies during psychiatric treatment in which they are used in higher doses than the doses used in the treatment of chronic pain syndromes (25 to 100 mg) recommend that TACs should be avoided in the elderly and patients with cardiomyopathies.

It is known that, in Brazil ⁴ and in the rest of the world ⁵, the incidence of neuropathic pain, as well as cardiovascular diseases, increases with age. Therefore, we have, on one hand, a drug with a good analgesic response in neuropathic pain, and on the other hand, the concern about possible deleterious cardiovascular effects. However, the literature lacks evidence proving the incidence of those effects in the doses used for pain relief.

The objective of this study was to evaluate the use of TACs in chronic pain syndromes and their electrocardiographic repercussions.

METHODS

After approval by the Ethics on Research Committee of the Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro (HUCFF/UFRJ) and signing of the informed consent, 40 patients of the Pain Treatment and Palliative Care Program (PTDCP, from the Portuguese), ages 18 years or older, with neuropathic pain were included in this study. Exclusion criteria were as follows: patients on class Ia anti-arrhythmic drugs (pro-arrhythmic action); consumptive syndromes, liver disease, unstable cardiomyopathies, major mood disturbances (depression, bipolar) disorders, and altered cognition. Fifty-two patients were enrolled in the study; however, 12 were excluded for the following reasons: the dose was reduced in four patients due to a non-cardiac collateral effect (somnolence); one presented persistent palpitation and the drug was discontinued; four did not attend follow-up appointments, and three started TACs before the baseline ECG. Twenty one patients were males and 19 females. Patients on amitriptyline or imipramine on doses equal or greater than 25 mg/day for relief of neuropathic pain participated in this study. Patients underwent three electrocardiograms (ECG), which were analyzed posteriorly: before beginning TACs, and 30 and 60 days after its onset. Standard 12-lead ECG, at a speed of 25 mm.sec^-1, was done with the patient at rest. The following parameters were measured and analyzed: HR (heart rate), PR, QRS, QT, QTc, QT dispersion, and QTc dispersion. As for the PR interval, measured from the beginning of the P wave to the beginning of the QRS, the highest value among the bipolar derivations in the frontal plane (D₁, D₂, D₃) was considered, and 0.21 sec was the upper normal limit ⁶. A QRS of up to 0.10 sec was considered normal. For the QT interval, it was established a value of up to 0.46 sec, in V₂ or V₃, by the Lepeschkin method ⁷. For the QT dispersion (normal up to 60 msec), it was calculated the difference between the lower and higher QT of the 12 leads. The Bazett formula (QTc = QT/RRsec^1/2) was used to calculate the QTc (QT interval corrected for the mean heart rate) ⁸. The QTc dispersion (DQTc — QTcmax — QTcmin) was also calculated.

For the statistical analysis, the results obtained for each parameter were evaluated by the Kolmogorov-Smirnov test, which did not reject the hypothesis of normalcy. Mean standard deviation and standard error were calculated. Analysis of Variance (ANOVA) for repeated measures was used to compare measurements along time (pre-, and 30 and 60 days of treatment). Paired Student t test was used to evaluate the progression of the doses of the drugs along the study. A level of significance of 5% was established for all statistical tests. The SPSS statistical program version 13.0 was used.

RESULTS

Table I shows the characteristics of all 40 patients regarding gender, age, use of imipramine or amitriptyline, preexisting diseases, and pattern of prior ECGs. Amitriptyline was used at a mean dose of 54.3 mg, and imipramine, 46.8 mg. Painful syndromes included: herniated intervertebral disk (17.5%), post-traumatic neuritis (17.5%), lumbosciatalgia (10%), post-herpetic and post-leprosy neuritis (7.5% each), and post-laminectomy syndrome, central pain and postoperative neuroma (5.0% each).

Heart rate, PR, QRS, QT, QTc, DQT, and DQTc of all 40 patients during the eight weeks of treatment with TACs were analyzed and the results only showed statistically significant differences in the variation of the HR and duration of the QRS (Table II).

When compared with the dose of the TACs, the QTc demonstrated statistically significant differences with the use of amitriptyline (Student t test — Table III). Due to the reduced number of patients on imipramine, confirmation of this information was not possible. Stratified analysis was done for: gender, age, baseline cardiomyopathy, baseline ECG, and type of TCA used (Tables IV, ^V, and ^VI).

DISCUSSION

The Pain Clinic of the Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro was opened in 1983 and it has a multidisciplinary team that includes anesthesiologists, psychiatrists, clinicians, physical therapists, and social workers. It treats oncology patients undergoing palliative care and patients with non-oncologic chronic pain. Tricyclic antidepressants are prescribed for approximately 40% of the patients with chronic pain followed-up by the Program, which justifies the importance of the present study.

Tricyclic antidepressants have been used for more than 40 years in the treatment of depression, and more than 20 years in the treatment of neuropathic pain, starting with the studies of Watson ⁹, Max ¹⁰, and Leijon ¹¹. In the decade of 1960, when their use became more common, heart block or arrhythmias were the main cause of death in cases of overdose.

As for their cardiac effects, they interfere with conduction, which can be seen in the electrocardiogram and electrophysiological studies, with increases in PR, QRS, and QTc intervals. However, those increases are seldom symptomatic in patients without heart disease ¹². More recently, it has been speculated that low doses of those drugs are not associated with additional risks, even in the elderly and patients with heart disease ¹³. The results of the present study corroborate those in the literature. However, it should be emphasized that the doses used in psychiatry are higher than those used for analgesia ^14,15, what can affect patients with heart disease ¹⁶ and the elderly ¹⁷. One of the rare publications on their safety in low doses is a meta-analysis of six studies comparing low doses of TACs (< 100 mg) with standard doses used in the treatment of depression (> 100 mg), showing the lower incidence of side effects in low doses ¹.

In this longitudinal, prospective study, antidepressants were used in maximal analgesic doses of 75 mg/day in a representative sample of the population as far as gender, pain syndrome, and mean dose of TACs are concerned.

Interferences with the HR, with a mild increase, were observed after 30 days of treatment (M₁), and this was statistically significant (Tabe II). The increase in heart rate begins at the onset of treatment, with a tendency for adaptation in approximately four weeks. This variation only affected females. At the end of the follow-up (M₂), a return to baseline levels was observed (p = 0.01). This transitory effect was not clinically significant, but it has been reported in the literature ¹⁸.

The duration of the QRS complex was discretely increased in M₁, with a small statistical significance (p = 0.049 and CI = 0.014-6.58). However, values in M₂ increased further when compared to baseline levels (M₀), with a p = 0.03 (CI 2.02-8.90) and without clinical repercussion (Table II). This small variation of the QRS was seen in elderly patients and patients with cardiomyopathies (Tables IV and ^V). QRSs complexes equal or greater than 120 msec were not observed until the end of the follow-up; this level according to the literature would indicate greater tendency for arrhythmia ¹⁹. In the present study arrhythmias were not observed on the electrocardiogram.

As for the baseline ECG, QRS changes were observed in patients whose baseline ECG was altered as well as in those with normal ECGs (Table IV). In this study, patients with prior conduction changes did not have greater variation of the QRS, which is not supported by the literature when TACs are used in antidepressant doses ²⁰.

It was demonstrated that change in the QRS occurred at the moment the highest dose was used. This supports the notion that the influence of this group of drugs on cardiac electrophysiology is mainly dose-dependent.

Evaluating the effects of different doses of TACS, this study demonstrated a significant increase in QTc during the use of 75 mg of amitriptyline (p = 0.04). On the other hand, a reduction in the QTc was observed with the use of 50 mg of imipramine, but this was not statistically important.

An increase in QT can lead to severe ventricular arrhythmias, according to Antzelevitch ²¹. QT dispersion (DQT) reflects regional differences in ventricular depolarization time. When the intrinsic heterogeneity of the ventricular myocardium is widened, it is reflected on a greater DQT. In the present study, QT dispersion did not increase significantly during treatment (Table III). Despite reports in the literature, which demonstrate the presence of cardiovascular complications, including heart blocks, with antidepressant doses of TACS, arrhythmias were not detected in this study ^22,23.

In cases of differences in the dose used, one could demonstrate an influence on the QTc, but only in cases treated with amitriptyline (Table III). But the reduced number of patients treated with imipramine (eight) did not allow the conclusion that this drug does not interfere with the QT interval. Elderly patients and women are more prone to TAC-induced increases of the QT interval ²⁴, which was not demonstrated in the present study.

To conclude, tricyclic antidepressants affect the conduction system, but without clinical significance in patients with heart disease and the elderly, because the doses used for analgesia of neuropathic pain were lower than 100 mg.

REFERENCES

• 01. Furukawa AT, McGuire H, Barbui C — Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ, 2002;325:991-995.
• 02. Moore A, Edwards J, Barden J et al. — Bandolier's Little Book of Pain. New York, Oxford, 2003.
• 03. Baldessarini RJ — Antidepressivos, em: Goodman & Gilman As Bases Farmacológicas da Terapêutica, 10Ş Ed., Rio de Janeiro, Guanabara Koogan, 2003;339-364.
• 04. Teixeira MJ, Teixeira WJ, Kraychete DC — Epidemiologia Geral da Dor, em: Teixeira MJ Dor: contexto interdisciplinar. 1Ş Ed., Curitiba, Maio, 2003;53-66.
• 05. Kareholp I, Brattberg G — Pain and mortality risk among elderly persons in Sweden. Pain, 1998;77:271-278.
• 06. Decacche W — ECG para o Clínico. 1Ş Ed. Rio de Janeiro: Revinter, 2004.
• 07. Lepeschkin E, Surawicz B — The measurement of the QT interval of electrocardiogram. Circulation, 1952;6:378-388.
• 08. Funck-Brentano C, Jaillon P — Rate-corrected QT interval: Techniques and limitations. Am J Cardiol,1993;72:17b-22b.
• 09. Watson CP, Evans RJ, Reed K — et al Amitriptyline versus placebo in postherpetic neuralgia. Neurology, 1982;32:671-673.
• 10. Max MB, Culnane M, Schafer SC et al. — Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology, 1987;37:589-596.
• 11. Leijon G, Boive J — Central post-stroke pain: a controlled trial of amitriptyline and carbamazepine. Pain, 1989;36:27-36.
• 12. Glassman AH, Rodrigues AI, Shapiro PA — The use of antidepressant drugs in patients with heart disease. J Clin Psychiatry, 1998;59(suppl 10):16-21.
• 13. Ray WA, Meredith S, Thapa PB et al. — Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther, 2004; 75:234-241.
• 14. Berger A, Dukes E, Edelsberg J et al — Use of tricyclic antidepressants in older patients with diabetic peripheral neuropathy. Clin J Pain, 2007;23:251-258.
• 15. Chen H, Lamer TJ, Rho RH et al — Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc, 2004;79:1533-1545.
• 16. Cohen HW, Gibson G, Alderman MH — Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. Am J Med, 2000; 108:2-8.
• 17. Bingefors K, Isacson D, Knorring LV et al — Antidepressant-treated patients in ambulatory care mortality during a nine-year period after first treatment. Br J Psychiatry, 1996;169:647-654.
• 18. Glasmann AH — Cardiovascular effects of antidepressant drugs update. J Clin Psychiatry, 1998;59(suppl 15):13-18.
• 19. Buckley NA, Chevalier S, Leditschke IA et al. — The limited utility of electrocardiography variables used to predict arrhythmia in psychotropic drug overdose. Critical Care, 2003;7:101-107
• 20. Roose SP, Glassman AH, Dalack GW — Depression, heat disease and tricyclic antidepressants. J Clin Psychiatry, 1989; 50: 12-18.
• 21. Antzelevitch C — Arrhythmogenic mechanisms pf QT prolonging drugs: is QT prolongation really the problem? J Electrocardiol, 2004;37(suppl):15-24.
• 22. Sadanaga T — Abnormal QT prolongation and psychotropic drug therapy in psychiatric patients: significance of bradycardia-dependent QT prolongation. J Electrocardiol, 2004;37:267-273.
• 23. Chow BJ, Gollob M, Birnie D — Brugada syndrome precipitated by a tricyclic antidepressant. Heart, 2005;91:651.
• 24. Morganroth J — A definitive or thorough phase 1 QT ECG trial as a requirement for drug safety assessment. J Electrocardiol, 2004;37:25-29.

Publication Dates

• Publication in this collection
  16 Feb 2009
• Date of issue
  Feb 2009

History

• Received
  24 June 2007
• Accepted
  12 Sept 2008