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Print version ISSN 0034-7094
On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.4 Campinas July/Aug. 2005
Methadone to treat non-oncologic neuropathic pain. Case reports*
Uso de la metadona en el tratamiento del dolor neuropático no oncológico. Relato de casos
Jeane Pereira da Silva Juver, M.D.I; Nubia Verçosa Figueiredo, M.D.II; Louis Barrucand, M.D.III; Mauricio de Assis Tostes, M.D.IV
IPós-Graduanda do Curso de Pós Graduação
em Cirurgia Geral - Setor Anestesiologia - Nível Mestrado, da Faculdade
de Medicina da UFRJ. Anestesiologista Responsável Técnica pelo Centro
de Cuidados Paliativos do Serviço de Hematologia e Oncologia Clínica
Hospital Municipal Cardoso Fontes
IIProfessora Adjunta e Doutora em Medicina do Departamento de Cirurgia da FM/UFRJ. Coordenadora da Graduação e Pós-Graduação em Anestesiologia da FM/UFRJ. Anestesiologista e Responsável pelo Ambulatório de Avaliação Pré-Anestésica do Hospital Universitário Clementino Fraga Filho (HUCFF) FM/UFRJ. Certificado de Área de Atuação em Dor SBA-AMB
IIIProfessor Titular de Patologia do Departamento de Anatomia Patológica da FM/UFRJ
IVMédico do Instituto de Psiquiatria e do Serviço de Psicologia Médica e Saúde Mental do HUCFF/UFRJ. Doutor em Medicina pela UFRJ
BACKGROUND AND OBJECTIVES:
This report includes seven patients with chronic non-oncologic neuropathic pain
who have not responded to classic approaches with tricyclic antidepressant and
anticonvulsant drugs. Oral methadone, a synthetic opioid similar to morphine,
is referred as alternative to treat neuropathic pain due to its non-competitive
antagonist action on NMDA receptors. This study aimed at evaluating methadone
to treat chronic non-oncologic neuropathic pain patients who have not responded
to classic approaches.
CASE REPORTS: Seven cases in which methadone dose was titrated in subsequent visits are presented. Pain severity according to facial scale, side effects and improved functional capacity were evaluated 1, 7, 14, 30 and 180 days after treatment beginning. There has been decrease in pain severity and in the incidence of side effects, such as constipation, sedation, nausea, headache and insomnia. There has been no euphoria, sweating, myoclonia, urinary retention, decreased libido and respiratory depression.
CONCLUSIONS: Patients responded satisfactorily to low dose medication, side effects were controlled with simple measures and there has been significant functional capacity improvement. In the conditions of this study, methadone was an effective, safe and low-cost option to treat non-oncologic neuropathic pain.
Key Words: ANALGESICS, Opioid: methadone; PAIN, Chronic: neuropathic; non-oncologic
JUSTIFICATIVA Y OBJETIVOS:
El relato incluye siete casos de pacientes con dolor neuropático crónico
no oncológico, que no habían logrado resultados satisfactorios con
los tratamientos clásicos con antidepresivos tricíclicos y anticonvulsivantes.
El uso de la metadona, opioide sintético, semejante a la morfina, por vía
oral, es referido como alternativa en el tratamiento del dolor neuropático
por su acción antagonista no competitiva sobre los receptores NMDA. El
objetivo de este estudio es evaluar el uso de la metadona en el tratamiento
de pacientes portadores de dolores crónicos de origen neuropático
no oncológico, que no mejoraron con los tratamientos clásicos.
RELATO DE LOS CASOS: Se presentan siete casos en los cuales la dosis de metadona fue titulada en consultas subsiguientes y los variables resultados de la intensidad álgica según la escala de aspectos, efectos colaterales y mejora de la capacidad funcional fueron analizados en el 1º, 7º, 14º, 30º y 180º días después del inicio del uso de la medicación. Hubo reducción de los resultados de la intensidad álgica y la ocurrencia de efectos colaterales como constipación, sedación, náuseas, cefalea e insomnio. No fueron observados efectos colaterales del tipo euforia, sudoresis, mioclonias, retención urinaria, reducción de la libido y depresión respiratoria.
CONCLUSIONES: Los pacientes presentaron respuesta considerada satisfactoria al uso de la medicación, en bajas dosis; control de los efectos colaterales con medidas simples y mejora representativa de la capacidad funcional. La inclusión de la metadona, en las condiciones de este estudio, se mostró una opción eficaz, segura y de bajo valor, para el tratamiento de los dolores de origen neuropáticos no oncológicos.
Pain is defined by IASP (International Association for the Study of Pain) as a disagreeable sensory and emotional experience associated to effective or potential tissue injury or described in such terms 1.
Pain may be classified in acute and chronic 1. Chronic pain is considered a disease when interfering with quality of life, thus requiring effective treatment to prevent the development of physical (muscle atrophy, decreased muscle strength, shortening and decreased elasticity of tendons and ligaments) or psychical (sleep disorders, anxiety and depression) sequelae. Due to these facts, the development of new treatment options is a matter of humaneness.
To support the clinic in understanding this phenomenon and as a justification for a treatment proposal, pathophysiology studies have classified the origin of pain as nociceptive or neuropathic 1-3.
Neuropathic pain leads to plastic neuronal changes including increased number of ion channels, changes in their patency and distribution; abnormal responses to catecholamines and N-methyl-D-aspartate (NMDA) receptors activation. These are excitatory receptors activated by glutamate and bound to a calcium ion channel. They are activated after repeated neuronal depolarizations and do not participate on normal transmission 4.
Classic drugs to treat neuropathic pain are antidepressants and anticonvulsants 5 in addition to anesthetic blocks in specific situations. However, some patients do not respond to treatment, either because there is no pain relief or because they do not tolerate side effects.
In the search for alternatives, studies with NMDA receptor antagonists have shown that they could be promising alternatives provided their side effects were controlled 6.
Based on pharmacological studies for the treatment of moderate to severe neuropathic pain, a synthetic opioid similar to morphine, namely methadone, which is an opioid receptor agonist with non-competitive antagonist action on NMDA receptors, was used 7-10.
Some unique characteristics of methadone metabolism are: lack of pharmacologically active metabolites; trend to maintain its effects after prolonged use; bioavailability and individualized excretion half-life. Methadone is extensively metabolized by the liver through the N-demethylation process into pharmacologically inactive metabolites which do not build up during renal failure and are not removed by hemodialysis. It crosses placental barrier freely and may cause withdrawal syndrome in neonates when mothers are given methadone during pregnancy. However, concentrations found in breast milk do not prevent breastfeeding 10.
This report aimed at evaluating the importance of methadone to treat chronic non-oncologic neuropathic pain patients who have not responded to classic approaches.
After the Institution's Research Ethics Committee approval, the therapeutic effects of methadone were observed in seven patients from the Ambulatory of Pain Treatment and Paliative Care, Collective Community Health Program, Hospital Universitário Clementino Fraga Filho (HUCFF), School of Medicine (FM) Universidade Federal, Rio de Janeiro (UFRJ), through a prospective study.
For subjective evaluation of pain severity, the one-dimension facial scale (FS) was used, in which scores are attributed to each face representation in ascending order. Zero corresponds to no pain and 4 to the worst possible pain (Figure 1), according to World Health Organization (WHO) criteria.
Inclusion criteria were patients: 1) with pain severity ³ 2 in FS; 2) non-oncologic neuropathic pain; 3) who have not improved at least 50% with classic approaches; 4) who have not improved their functional capacity or who could not tolerate side effects of tricyclic antidepressants and/or anticonvulsants; 5) aged above 18 years; 6) of both genders.
Exclusion criteria were patients: 1) with high degree of pain amplification; 2) pregnant or breastfeeding; 3) without functional improvement after beginning of treatment.
Methadone dose was titrated after the first visit until pain severity was decreased and functional and side effects were improved. These variables were evaluated 7, 14, 30 and 180 days after treatment beginning.
Functional improvement was evaluated by the following parameters: self-care, daily working and rehabilitation activities, mood, and social, sexual and family relationships.
Patients were told what to do in case of adverse effects.
Oral methadone dose was titrated in the first visit using 2.5 mg methadone every 30 minutes until score 1 (mild pain) or 0 (no pain) was reached. At home, if pain intensity reached score 2 (moderate pain), patients could use methadone dose titrated during visit with minimum intervals of 4 hours.
Frequency of methadone administration and functional capacity parameters were recorded in the home follow up record standardized by the Pain Treatment and Palliative Care Program (Chart I), which should be taken by patients to every ambulatory visit.
During the second visit, that is, seven days after, methadone dose was calculated for two daily administrations. Side effects were reported and specific treatment was started when needed. At third evaluation (14th day), previous visit data were re-evaluated and associated to patients' functional capacity changes. In the last visit (180th day), dose stabilization and functional capacity changes were evaluated.
Case 1 - Female patient referring pain in the third right finger in shock, with spontaneous onset, recurrent and FS score 3, in addition to hypoesthesia in the ipsilateral tenar region. At evaluation, patient was under irregular use of COX2 inhibitor and carbamazepine without symptoms relief. Domestic servant, patient was licensed by Social Security after diagnosis. Patient would carry out daily activities with difficulty (take care of home, washing, cooking). Patient lives alone, close to relatives with whom she refused to have contact for considering herself irritated as a consequence of the surgery and of the pain that still persisted. Patient would seldom look for entertainment and avoided social contact due to her financial condition and "physical disability". Patient is mother of a male adolescent who lives with the maternal grandmother in her hometown with whom she maintains sporadic contact. Currently she had no sexual partner. During treatment she looked for a new job, improved her self-esteem, family and social contact and started planning for the future. Patient evolved with pain control with stable methadone doses (5 mg/day). Major side effect was sedation.
Case 2 - Male patient with herpes zoster for two years, complaining of continuous burning pain in the inguinal region, topography of L1 and L2 to the right, with periods of spontaneous exacerbation and FS score 2. There were no reports on associated symptoms. Carbamazepine had been withdrawn due to intolerance to side effects. Analgesic blocks were started and then interrupted due to unsatisfactory response. Patient is retired with informal carpenter activities to complement income. Patient lives with his wife with whom he has good relations and active sexual life. Patient has three sons who live nearby and with whom he has good relationships. Patient reported being unhappy and needing to be by himself due to disabling pain. He mentioned that going back to work would be the solution for his unhappiness and that he was willing to solve his pain problem. At the end of the treatment he had returned to informal activities performing minor tasks. He was concerned with meeting his future goals due to the employment crisis the country was going through. Pain was controlled with daily 10 mg methadone. Patient referred intestinal constipation during treatment. This adverse effect was controlled with laxatives.
Case 3 - Female patient with continuous and "painful" FS score 4 pain for 4 months, with episodes of shock pain. Patient has reported muscle strength decrease, sweating and hyperemia, at ulnar nerve topography to the left, secondary to surgical procedure to correct ulnar nerve lesion at forearm medium third, caused by cutting wound. At evaluation, patient was under irregular use of COX2 inhibitor and paracetamol. Dressmaker, she would do minor manual works to complement income however she had to stop them due to pain. Separated from the companion for ten years she lived with the adolescent daughter. Patient had difficulties to perform domestic activities (washing, cleaning) needing her daughter's help. This made her feel disabled and brought lots of unhappiness for feeling that this "dependence" could impair her daughter's social and sentimental life. During treatment she accepted the suggestion of including physical therapy exercises to her daily life and has returned to informal work. In this case, pain was controlled with 20 mg/day methadone. Side effects were intestinal constipation, sedation and headache.
Case 4 - Female HIV patient referring lower limbs continuous, pain, at weight, FS score 4 for two years, without relieving or worsening factors, associated to paresthesia which would impair ambulation. At evaluation she was under irregular use of codeine associated to paracetamol and anti-retroviral drugs. Patient lived with parents, was retired and avoided social contact for considering that her disease was difficult to deal with, moreover when, in addition to physical changes, there were painful symptoms compromising her good relationship with other people. Patient reported fear of no longer being able to walk as a consequence of pain, fact which would bring lots of suffering because she would depend on her parents whom she considered tired of so much suffering. During treatment there has been improved family and social relationship leading to the search for leisure activities. Pain was relieved with 10 mg/day methadone. Side effects were nausea and headache.
Case 5 - Female patient with "painful", continuous, FS score 3 pain, which would worsen with movements and improve at rest, associated to paresthesia of right forearm ulnar edge. Patient was under irregular use of analgesic and anti-inflammatory drugs without resolution. Patient is a nurse. After surgeries to treat ulnar synostosis, patient was licensed by Social Security. Patient lived with her companion and her daughter. Matrimonial problems were exacerbated after surgeries and her quitting her job. Patient reported her disease and problems with rage. At evaluation, although living with her companion, she denied having active sexual life. During last visit she was under physiotherapic follow up, had medium and long-term plans and was looking for leisure activities together with the daughter. Pain was controlled with daily methadone doses (20 mg). Side effect was intestinal constipation controlled with laxatives.
Case 6 - Male patient with continuous, at weight, diffuse (C6 to S4), FS score 2 pain with episodes of shock pain especially on lower limbs, with major worsening with ambulation and associated to diffusely distributed paresthesia and bilateral plantar hyperesthesia. At evaluation patient was not taking medication because he had withdrawn at his own judgment the use of analgesics, antidepressants and anticonvulsants. Patient lived with wife and two adult children with whom he reported good relationships and cooperation among all. Patient blamed the disease for all his problems because when he was able to work and had money he was not forced to be with his wife's relatives. In other moments he would refer to the disease as punishment to his arrogant personality as boss, husband and father. During treatment he started morning walks without pain exacerbation after exercising. He was more prone to try to control family problems as acquired more autonomy. Pain was decreased with 10 mg/day methadone and side effect was insomnia.
Case 7 - Male patient with lower limbs burning pain, FS score 4, for four years, with episodes of shock pain followed by paresthesia, hyperesthesia and allodynia. Pain would worsen with movements and improve at rest. Patient had similar symptoms in upper limbs. Patient was under no specific treatment after having withdrawn anticonvulsants and antidepressants. Patient lived with his companion with whom he had no children by fear of his disease being hereditary, fact that caused matrimonial problems. Patient denied having active sexual life and avoided social contact due to the stigmatizing character of his disease, especially coffee and milk stains and strabismus. Patient reported changes in personal hygiene habits due to allodynia, which would further impair his social and interpersonal relationships. During treatment patient reported being willing to return to physical therapy to readapt to the marketplace. Patient has returned to sexual activities and improved his self-care activities. Pain was controlled with 20 mg/day methadone and reported side effect was nausea during the treatment.
Age, gender, pain evolution and causes are shown in table I. FS pain scores before methadone (FSBM) and after methadone (FSAM) are shown in table II. Relationship between methadone doses and side effects, such as constipation, sedation, nausea, headache and insomnia are shown in table III. There were no euphoria, sweating, myoclonia, urinary retention, decreased libido and respiratory depression.
Pain severity was evaluated through patients' reports using scales which act as parameters for analgesic dose quantification and respective complementation. The one-dimension facial scale, considering pain severity alone, is easy to understand and may be used for children and adults 11. It was standardized by the Pain Treatment and Palliative Care Program, HUCFF.
Patients were evaluated in regular 30-day intervals throughout the study. Data obtained at 30 days were the 4th evaluation and values obtained at 180 days were the 5th evaluation. It is worth stressing that patients continued to be followed by professionals of the Pain Treatment and Palliative Care Program after study completion.
Our cases have shown 50% or more decrease in pain severity during treatment with methadone, with doses considered low. Mean 12.14 mg/day dose (minimum of 5 mg and maximum of 20 mg/day) divided in two daily doses, is considered a low dose according to data in the literature where doses vary from 60 to 80 mg/day divided in three to four 20 mg doses 12.
Side effects were tolerated or treated with adjuvant drugs. There has been resolution or decreased severity in some cases, thus not impairing quality of life. Such behavior may be attributed to titration of the opioid dose 13.
Most common opioid side effect is intestinal constipation being mandatory the simultaneous prescription of diet and laxative medication. This posture was not adopted with our patients. In the presence of such effect, symptoms were resolved with adjuvant drugs, senna extract and associations (Tamarine®), which is a described and accepted approach 14.
Scientific studies have observed lower incidence of nausea and sedation with methadone as compared to morphine 10. This effect has been also observed in our group, however with no need for specific treatment. Tolerance to these effects may be observed with prolonged treatment.
Insomnia may be observed in 10% to 20% of patients using methadone as maintenance drug 15. The same frequency was observed in our cases.
Although there has been headache referred by two patients after methadone, no similar report was found in our references.
In analyzing improved functional capacity after opioids, excellent results were observed in all patients. No scores were used to evaluate this variable. This statement was based on reports on changes in social, sexual, family and work relationships, on the return to rehabilitation activities, on easily performing daily activities and on short and long term plans.
The possibility of new therapies is seen as a major option for pain relief. Results have shown the diversity of diseases that may be followed by neuropathic pain. The possibility of treating these patients throughout different medical specialties reinforces the need for researches and studies to clarify the details of its physiopathology, which still remain unexplained. Methadone may be a low cost option to treat non-oncologyc pain.
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Dra. Jeane Pereira da Silva Juver
Address: Rua Caricé, nº 285 Ap 205, Bancários, Ilha do Governador
ZIP: 21920-100 City: Rio de Janeiro, Brazil
Submitted for publication December
Accepted for publication April 6, 2005
* Received from Programa de Pós-Graduação em Cirurgia Geral - Setor Anestesiologia do Departamento de Cirurgia da Faculdade de Medicina (FM) da Universidade Federal do Rio de Janeiro (UFRJ)