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Equivalency of Tricyclic Antidepressants in Openlabel Acta Neurol Scand DOI: 10.1111/ane.12169 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA Equivalency of tricyclic antidepressants in open-label neuropathic pain study Liu W-Q, Kanungo A, Toth C. Equivalency of tricyclic W.-Q. Liu, A. Kanungo, C. Toth antidepressants in open-label neuropathic pain study. Department of Clinical Neurosciences, the Hotchkiss Acta Neurol Scand: DOI: 10.1111/ane.12169. Brain Institute, and the University of Calgary, Calgary, © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. AB Canada Objectives – To compare adverse effects, tolerability and efficacy of the tricyclic antidepressants (TCAs) amitriptyline and nortriptyline in management of neuropathic pain due to peripheral neuropathy (PN). Materials & Methods – We performed a prospective open-label flexible-dosing comparison of monotherapy or adjuvant therapy using amitriptyline or nortriptyline in PN-associated neuropathic pain. Primary outcomes were quantitative adverse effects and discontinuation rates. Secondary outcomes assessed changes in pain severity, quality of life, disability, sleep efficacy, mood and anxiety, and global improvement. Assessments occurred at 3 and 6 months after initiation. Our hypothesis was that nortriptyline would have better tolerance than amitriptyline. Results – A total of 228 PN patients were enrolled approximately equally for monotherapy and adjuvant therapy. Adverse effects and discontinuation rates were similar between amitriptyline and nortriptyline interventions. Weight gain was more common with amitriptyline, while nortriptyline use was Key words: chronic pain C10.597.617.258; polyneuropathy C10.668.829.800; tricyclic associated with greater prevalence of dry mouth. Secondary outcome antidepressants D27.505.954.427.700.122.055 measures were similar in both groups, demonstrating improvement from baseline. Conclusions – Amitriptyline and nortriptyline are Cory Toth, Department of Clinical Neurosciences, HMRB 155, University of Calgary, Hotchkiss Brain equivalent for overall adverse effects and discontinuation rates. Either Institute, 3330 Hospital Dr. NW, Calgary, AB, Canada TCA should be equally considered for use in neuropathic pain due to T2N 4N1 PN. When used as monotherapy or as part of adjuvant therapy, either Tel.: (403) 220-8831 TCA can be expected to provide approximately 23–26% visual analog Fax: (403) 283-8731 scale pain reduction if tolerated. Discontinuations due to inefficacy or e-mail: [email protected] adverse effects can be anticipated in 26–37% of patients initiated on either TCA for PN-associated neuropathic pain. Accepted for publication July 8, 2013 reuptake inhibition with additional sodium and Introduction calcium channel blockade activity (7). Antihistam- Due to a lesion or disease of the somatosensory inergic and anticholinergic effects likely contribute nervous system (1), neuropathic pain affects up to their adverse effects including dry eyes and to 8% of the general population (2). In patients mouth, dizziness, confusion, and urinary reten- with peripheral neuropathy (PN), neuropathic tion. The two most commonly studied TCAs are pain occurs in up to 50% of cases (3), accompa- amitriptyline and nortriptyline; amitriptyline is a nied by hyperesthesia, allodynia, paresthesias, tertiary amine while nortriptyline is a secondary and motor and coordination deficits. Chronic amine and it is the demethylated metabolite of neuropathic pain due to PN significantly compro- amitriptyline. Anecdotally, nortriptyline is touted mises quality of life (4) and frequently requires to have fewer adverse effects than amitriptyline pharmacotherapy (3). (8), possibly due to less anticholinergic activity Tricyclic antidepressants (TCAs) are first-line (7), while retaining similar efficacy. Both amitrip- agents for neuropathic pain treatment in many tyline (9, 10) and nortriptyline (11) have been guidelines (5) with Level B evidence (6). TCAs studied using randomized controlled studies in have strong serotoninergic and noradrenergic forms of neuropathic pain, but outside of a study 1 Liu et al. examining their use in post-herpetic neuralgia (8), and specificity, was used to identify clinical likeli- there are no other existing head-to-head compari- hood of neuropathic pain presence – only those sons of amitriptyline and nortriptyline in condi- patients with a score of ≥4 were enrolled (13). tions of neuropathic pain. Severity of PN was assessed using the Toronto We hypothesized that nortriptyline would be Clinical Scoring System (TCSS) as described pre- better tolerated than amitriptyline in the treat- viously (12) – this scale emphasizes sensory defi- ment of neuropathic pain associated with PN. cits related to PN. Investigations to determine We performed a prospective randomized open- etiology of PN were conducted (12). label comparison of amitriptyline vs nortriptyline We prospectively examined and followed 5 in the treatment of PN-associated neuropathic cohorts: monotherapy with amitriptyline, mono- pain as monotherapy or adjuvant therapy. therapy with nortriptyline, adjuvant therapy with amitriptyline, adjuvant therapy with nortriptyline, and a control group of patients receiving no Materials and methods pharmacological therapy for neuropathic pain by their own choice. Subjects choosing to receive Patient assessment pharmacotherapy were randomized to amitrip- We prospectively evaluated patients with neuro- tyline or nortriptyline via concealed envelope pathic pain related to PN in a tertiary care neu- allocation. Once randomized, open-label manage- romuscular clinic. Methods of recruitment, ment was initiated with both patient and investi- assessment, and management have been previ- gator aware of allocation. Flexible dosing was ously described (12). Ethical approval was permitted to maximize pain relief and tolerability received from the Conjoint Health Research Eth- using previously described protocols (12). Our ics Board at the University of Calgary. Informed primary endpoint was tolerability based on inci- consent was obtained from all participants. dence of the reported adverse events and time to Patients with PN-associated neuropathic pain discontinuation of either TCA. Secondary end- were asked, ‘Do you have pain or discomfort points included changes in pain severity based over your feet and legs on a near-daily basis for upon visual analog scale (VAS), quality of life more than 6 months’? All patients responding analyzed using EuroQol 5 Domains (EQ-5D), dis- positively with a clinical picture consistent with ability examined with the Short Form 36 health neuropathic pain and presence of PN were survey (SF36), sleep efficiency evaluated by the enrolled. The Douleur Neuropathique en 4 ques- Medical Outcomes Sleep Study Scale (MOSSS), tions (DN4) questionnaire, with good sensitivity aspects of pain and function using the modified 339 PN Patients with NeP 111 Patients Unable to Participate Screened • Refused to Complete Questionnaires 228 PN Patients with NeP to have therapy initiated 89 Patients Receiving 106 Patients Receiving 33 Patients Chose to Amitriptyline Nortriptyline Receive No Therapy 42 Patients 47 Patients 50 Patients 56 Patients Starting Add on Starting Add on Monotherapy Amitriptyline Monotherapy Nortriptyline Three Month Follow Up Visit 37 Patients 39 Patients 38 Patients 46 Patients Continuing Continuing Continuing Continuing 33 Patients Continuing to Amitriptyline Amitriptyline Nortriptyline Nortriptyline Receive No Therapy Monotherapy Adjuvant Monotherapy Adjuvant Therapy Therapy Six Month Follow Up Visit 36 Patients 34 Patients 34 Patients 41 Patients Completed Completed Completed Completed 33 Patients Continuing to Amitriptyline Amitriptyline Nortriptyline Nortriptyline Receive No Therapy Monotherapy Adjuvant Monotherapy Adjuvant Therapy Therapy Figure 1. Summary of patient flow during study. 2 Amitriptyline and nortriptyline for pain Brief Pain Inventory (BPI) scores, and mood and severity. Patients were weighed and electrocardio- anxiety analyzed using Hospital Anxiety and grams were performed at the baseline, 3- and 6- Depression Scale (12). All outcomes were estab- month visits. Electrocardiograms were examined lished at baseline and after 6 months post-inter- for heart rate and corrected QT intervals. An vention (12), while a 3-month visit determined additional telephone call was conducted at adverse effects, tolerability, and VAS for pain 1 week after initiation to examine for adverse Table 1 Clinical features and baseline characteristics of patient cohorts studied Amitriptyline (n = 89) Nortriptyline (n = 106) Control Group Monotherapy Adjuvant Monotherapy Adjuvant (No Pharmacological Clinical features (n = 42) Therapy (n = 47) (n = 50) Therapy (n = 56) Therapy) (n = 33) Age (Mean Æ SD) 58 Æ 11 56 Æ 10 60 Æ 961Æ 12 61 Æ 12 Female sex (%) 26 (62) 30 (64) 30 (60) 32 (57) 19 (58) Duration of NeP symptoms 17 Æ 12 19 Æ 15 19 Æ 15 20 Æ 17 24 Æ 19 (months), mean Æ SD Age of initiation of NeP 59 Æ 10 59 Æ 13 61 Æ 14 63 Æ 15 63 Æ 16 (years), mean Æ SD Etiology of PN Idiopathic 7 8 6 9 5 Diabetes mellitus 10 15 17 15 10 Cobalamin deficiency 8 6 12 8 5 Monoclonal gammopathy of 42 24 3 uncertain significance Excessive alcohol intake 2 5 3 6 1 Immune-mediated 3 3 3 5 3 Hereditary 2 2 3 3 1 Other 6 6 4 6 5 TCSS 12.6 Æ 4.0 12.1 Æ 3.7 11.9 Æ 3.8 13.0 Æ 3.6 12.6 Æ 4.6 Pre-existing NeP Therapies, number N/A Carbamazepine (n = 4), N/A Carbamazepine (n = 7), N/A of patients using and 300 Æ 141 mg/d 420 Æ 128 mg/d average dose Valproic Acid
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