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The tricyclic antidepressants have long been a tool in the physician's armament for numerous indications, the most prominent of which being depression. Although their efficacy and side effects have been well documented, less known is their abuse. Prior literature has discussed this more for the tertiary amines such as amitriptyline, but currently, there are no documented cases of abuse with the secondary amine nortriptyline. This article reviews the prior literature in regard to tricyclic antidepressants and anticholinergics as substances of abuse, the proposed mechanisms of this, and susceptible populations, as well as a case review of a patient who admitted to using nortriptyline for its "buzz."

First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline-morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate-severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate-severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline-morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.

Background: Cervical radicular pain is a major cause of disability. No studies have been published comparing different types of nonsurgical therapy., Methods: A comparative-effectiveness study was performed in 169 patients with cervical radicular pain less than 4 yr in duration. Participants received nortriptyline and/or gabapentin plus physical therapies, up to three cervical epidural steroid injections (ESI) or combination treatment over 6 months. The primary outcome measure was average arm pain on a 0 to 10 scale at 1 month., Results: One-month arm pain scores were 3.5 (95% CI, 2.8 to 4.2) in the combination group, 4.2 (CI, 2.8 to 4.2) in ESI patients, and 4.3 (CI, 2.8 to 4.2) in individuals treated conservatively (P = 0.26). Combination group patients experienced a mean reduction of -3.1 (95% CI, -3.8 to -2.3) in average arm pain at 1 month versus -1.8 (CI, -2.5 to -1.2) in the conservative group and -2.0 (CI, -2.7 to -1.3) in ESI patients (P = 0.035). For neck pain, a mean reduction of -2.2 (95% CI, -3.0 to -1.5) was noted in combination patients versus -1.2 (CI, -1.9 to -0.5) in conservative group patients and -1.1 (CI, -1.8 to -0.4) in those who received ESI; P = 0.064). Three-month posttreatment, 56.9% of patients treated with combination therapy experienced a positive outcome versus 26.8% in the conservative group and 36.7% in ESI patients (P = 0.006)., Conclusions: For the primary outcome measure, no significant differences were found between treatments, although combination therapy provided better improvement than stand-alone treatment on some measures. Whereas these results suggest an interdisciplinary approach to neck pain may improve outcomes, confirmatory studies are needed.

We present a case report of novel variants of CYP2D6 and CYP2C19 identified in a patient who experienced adverse effects during antidepressant therapy. CYP2D6 DNA sequencing revealed that the patient was most likely an intermediate metabolizer, owing to the presence of a novel variant (2579C>T), which gives rise to a premature stop codon in exon 5. Because defects in CYP2C19 may also be important, we sequenced the promoter region and all exons of CYP2C19 and identified a cluster of three novel variants (-13G>A, 7C>T and 10T>C) around exon 1, as well as the more common CYP2C19*2 allele. The presence of multiple genetic lesions in CYP2C19 implies that this patient is potentially a CYP2C19 poor metabolizer, and this was confirmed by haplotype analysis. Combined impairment of CYP2D6 and CYP2C19 activities, we believe, may have contributed to the development of the observed drug responses in the present report.

Background: Nortriptyline and other tricyclic antidepressants are widely used in the treatment of depression. They are also used in chronic pain syndromes such as vulvodynia. We report a case of pityriasis rosea (PR)-like eruption in a young woman who was treated with oral nortriptyline for vulvodynia., Case Report: The patient presented with photosensitivity and erythematous, well-defined, oval papules and patches, with fine collarettes of scale on the dorsal hands, upper arms, and trunk. She showed a complete resolution of her rash with discontinuation of nortriptyline, thereby supporting the diagnosis of a drug-induced reaction., Comment: Pityriasis rosea-like drug eruptions have been associated with numerous medications, including angiotensin-converting enzyme inhibitors, antirheumatic drugs, lithium, and, more recently, biologics such as imatinib, adalimumab, and etanercept. A literature review did not reveal an association between PR-like drug eruptions and tricyclic antidepressants such as nortriptyline. We report a case of PR-like drug reaction to nortriptyline for clinical interest.

Background: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care., Methods: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks., Results: Nortriptyline was superior to placebo for the change in HAM-D (p < 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p < 0.079). Response rates favored nortriptyline (p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated., Conclusions: Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors.

Background: The use of double-blind designs, normally the criterion standard of clinical trials, is impossible when comparing medication therapy to procedural therapies for depression. In the Consortium for Research in Electroconvulsive Therapy (CORE) trial, depressed patients recently remitted with electroconvulsive therapy (ECT) were randomly assigned to receive continuation therapy with either ECT or medications. The purpose of this article is to describe the design characteristics and challenges of the trial and of our method of dealing with the lack of double-blind outcome assessment., Methods: The primary outcome measure was time to relapse of depression in the continuation phase. We developed a method to achieve partial blinding of depressive severity assessment. This consisted of videotaping the structured interviews, having the video tapes co-rated by personnel not involved in the patient's care, and a videotape-tracking maneuver so that the assessor of the videotapes could be blinded to phase and type of treatment., Results: We enrolled 624 patients into the initial treatment phase of the trial. Of these, 201 met criteria for randomization into the second, continuation phase. Our videotape-tracking maneuver to reduce bias in outcome assessment worked well during the trial., Conclusions: The CORE study is the first multicenter, randomized controlled trial of continuation ECT in the relapse prevention of major depressive episodes. We successfully recruited a large number of severely depressed patients into a 6 month trial and used a method of reducing bias that might result from lack of blinding.

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25-100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was, 14% for nortriptyline (95% CI=[-2%, 30%]), 7% for morphine (95% CI=[-8%, 22%]), and 7% for the combination treatment (95% CI=[-4%, 18%]). Mean doses were: nortriptyline alone, 84+/-24.44 (SD) mg/day; morphine alone, 62+/-29 mg/day; and combination, morphine, 49+/-27 mg/day plus nortriptyline, 55 mg+/-33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.

This study examined the effect of antidepressants in preventing depression after stroke. Nondepressed poststroke patients (N = 48) were randomly assigned to receive nortriptyline, fluoxetine, or placebo for 3 months by using double-blind methodology and were followed-up for 21 months by using a naturalistic design. During the treatment period, one minor depression developed in the nortriptyline group (n = 13 at 3 months), one minor depression developed in the fluoxetine group (n = 13), and five minor depressions developed in the placebo group (n = 15; p <.05). When treatment was discontinued, nortriptyline-treated patients were more likely to develop depression and had significantly more severe depressive symptoms during the next 6 months compared with patients in the other two groups. Both nortriptyline and fluoxetine appeared to be efficacious in preventing depression after stroke. However, nortriptyline produced an increased vulnerability to depression for more than 6 months after it was discontinued. This finding suggests the need to extend prophylactic treatment and monitor patients carefully after the discontinuation of nortriptyline.

Unlabelled: OBJECTIVE (BACKGROUND): Amitriptyline (AT) is a standard therapy for postherpetic neuralgia (PHN). Our hypothesis was that nortriptyline (NT), a noradrenergic metabolite of AT, may be more effective., Methods: A randomized, double-blind, crossover trial of AT versus NT was conducted in 33 patients., Results: Thirty-one patients completed the trial. Twenty-one of 31 (67.7%) had at least a good response to AT or NT, or both. We found no difference with regard to relief of steady, brief, or skin pain by visual analog scales for pain and pain relief; mood; disability; satisfaction; or preference between the two drugs. Intolerable side effects were more common with AT. Most patients (26/33) were not depressed, and most responding showed no change in rating scales for depression despite the occurrence of pain relief., Conclusions: We concluded that this study provides a scientific basis for an analgesic action of NT in PHN because pain relief occurred without an antidepressant effect, and that although there were fewer side effects with NT, AT and NT appear to have a similar analgesic action for most individuals.

To assess the efficacy of nortriptyline, a tricyclic antidepressant, as an analgesic in chronic back pain without depression, we conducted a randomized, double-blind, placebo-controlled, 8-week trial in 78 men recruited from primary care and general orthopedic settings, who had chronic low back pain (pain at T-6 or below on a daily basis for 6 months or longer). Of these 57 completed the trial; of the 21 who did not complete, four were withdrawn because of adverse effects. The intervention consisted of inert placebo or nortriptyline titrated to within the therapeutic range for treating major depression (50-150 ng/ml). The main outcome endpoints were pain (Descriptor Differential Scale), disability (Sickness Impact Profile), health-related quality of life (Quality of Well-Being Scale), mood (Beck Depression Inventory, Spielberger State Anxiety Inventory, Hamilton Anxiety/Depression Rating Scales), and physician rated outcome (Clinical Global Impression). Reduction in pain intensity scores was significantly greater for participants randomized to nortriptyline (difference in mean change 1.68, 95%-0.001, CI -3.36, P = 0.050), with a reduction of pain by 22% compared to 9% on placebo. Reduction in disability marginally favored nortriptyline (P = 0.055), but health-related quality of life, mood, and physician ratings of overall outcome did not differ significantly between treatments. Subgroup analyses of study completers supported the intent-to-treat analysis. Also, completers with radicular pain on nortriptyline (n = 5) had significantly (P < 0.05) better analgesia and overall outcome than did those on placebo (n = 6). The results suggest noradrenergic mechanisms are relevant to analgesia in back pain. This modest reduction in pain intensity suggests that physicians should carefully weigh the risks and benefits of nortriptyline in chronic back pain without depression.

Objective: Depression is a prevalent and chronic condition in diabetes and is associated with poor glucose regulation and poor compliance with diabetes treatment. This investigation evaluated the effects of nortriptyline on depression and glycemic control to see whether depression in diabetes is treatable and whether restoring mental health contributes to improved medical outcome., Method: Sixty-eight diabetic patients with poor glycemic control, 28 of whom had active major depression (DSM-IIIR), completed a randomized, placebo-controlled, double-blind trial involving 8 weeks of treatment with nortriptyline targeted to therapeutic plasma levels (50-150 ng/ml). Depression improvement was determined with the Beck Depression Inventory; glucose control was measured by glycated hemoglobin levels. Compliance behavior was assessed using medication dispensing devices and glucometers equipped with electronic memory., Results: The reduction in depression symptoms was significantly greater in depressed patients treated with nortriptyline compared with those receiving placebo (-10.2 vs -5.8, p = .03). Nortriptyline was not statistically superior to placebo in reducing glycated hemoglobin of the depressed subjects (p = .5). However, path analysis indicated that the direct effect of nortriptyline was to worsen glycemic control whereas depression improvement had an independent beneficial effect on glycated hemoglobin. These findings were not explained by the relationships of nortriptyline treatment to weight change (r = -0.21, p = .31) or depression improvement to compliance with the protocol for self-monitoring of blood glucose (r = 0.01, p = .97)., Conclusions: Major depression in diabetic patients can be effectively treated with nortriptyline at the expense of a direct hyperglycemic effect. Path analysis demonstrated a treatment-independent effect of depression improvement on glycemic control, suggesting that a more ideal antidepressant agent may both restore mental health and improve medical outcome.

We report a case of hepatic injury after treatment with nortriptyline in a therapeutic dose. There were symptoms of hepatitis and increased prothrombin time, serum alanine aminotransferase and alkaline phosphatases. The patient recovered after discontinuation of the drug.

The effectiveness of amitriptyline in relieving neuropathic pain following treatment of breast cancer was studied in 15 patients in a randomised, double-blind placebo-controlled crossover study. The dose was escalated from 25 mg to 100 mg per day in 4 weeks. The placebo and amitriptyline phases were separated by a 2-week wash-out period. Visual analogue and verbal rating scales were used for the assessment of pain intensity and pain relief. Other measures included the number of daily activities disturbed by the pain, the Finnish McGill Pain Questionnaire, adverse effects, anxiety, depression, pressure threshold and grip strength. Amitriptyline significantly relieved neuropathic pain both in the arm and around the breast scar. Eight out of 15 patients had a more than 50% decrease in the pain intensity ('good responders') with a median dose of 50 mg of amitriptyline. The 7 patients who had a less than 50% effect had drug concentrations equaling those of the good responders. The 'poor responders' reported significantly more adverse effects with amitriptyline and placebo than the good responders. It is concluded that amitriptyline effectively reduced neuropathic pain following treatment of breast cancer. However, the adverse effects of amitriptyline put most of the patients off from using the drug regularly.

Using nortriptyline as an example of a typical tricyclic antidepressant, I studied the relation between the steady-state concentration/dose ratio (C/D) and the performance of therapeutic drug monitoring (TDM), with a focus on the frequency of serum concentrations located in the therapeutic interval. A TDM database comprising 1,214 patients, of whom 619 patients had more than one sample taken, was used. The median C/D value for the patients was 4.05 [nM]/mg with 5th and 95th percentiles of 1.80 and 9.60, respectively. A total of 18.6% of the patients with C/D values below the 5th percentile had serum concentrations in the therapeutic interval at the first occasion, increasing to 49% for the average of the succeeding samples. These values were lower than those for the total group, 60.4 and 68.9%, respectively. For those with C/D values exceeding the 95th percentile, 36.2% had initial serum concentrations in the therapeutic interval, increasing to 66.3% for the average of succeeding samples. Only 11 patients (0.9%) had very high initial serum concentrations (> 1,200 nM). Thus patients with low C/D values are at risk of being underdosed, even after successive samples, whereas adequate dose correction is more likely to be implemented for those with average or high C/D values. Saturation kinetics for those with low C/D values was not a problem of clinical significance. Neither was lack of steady-state at the first occasion a problem for those with high C/D values (suspected poor metabolizers).

A 54-year-old woman with hyperprolactinemia and amenorrhea that occurred with phenothiazine and tricyclic antidepressant use developed a stage IBG2 endometrial adenocarcinoma. This is believed to be the first case reported of endometrial carcinoma associated with drug-induced hyperprolactinemia.

A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried out in patients with painful diabetic polyneuropathy. A visual analog scale was used to evaluate the relief of pain or paresthesia. Significant relief of both pain and paresthesia was obtained with this combination. The differences were statistically significant. Side effects were frequent but not usually severe enough to lead to cessation of these medications.