Doses Of Amitriptyline Research Articles

Subchronic Amitriptyline Influences Open-field Behaviours and Spontaneous Working-memory in Healthy Mice

Objective: We assessed the effects of amitriptyline on open-field locomotion, stereotypic behaviours and spatial working-memory in healthy mice. Method: Five groups of mice were administered vehicle (distilled water), scopolamine (2 mg/kg), or one of three doses of amitriptyline (5, 10 and 15 mg/kg) for 21 days. Behaviours were assessed after the first and final dose of treatment. Result: Administration of the first dose of amitriptyline was associated with enhanced open-field horizontal locomotion, rearing and grooming; with repeated administration, there was suppression of horizontal locomotion and rearing. A dose-related decrease in Y-maze and radial-arm maze spatial working-memory was also observed after repeated administration. Compared to scopolamine, amitriptyline was associated with a significant reduction in open-field behaviours, but a significantly-higher spatial working-memory score. Conclusion: Repeated administration of amitriptyline in healthy mice was associated with suppression of locomotion and grooming; working-memory deficits were also observed. However, working-memory task performance is significantly better than the scopolamine group.

Enhancement of Antinociceptive Effect by Co-administration of Amitriptyline and Crocus Sativus in a Rat Model of Neuropathic Pain.

The aim of this study was to evaluate the anti-nociceptive effects of a low, sub-effective dose of amitriptyline, in combination with the different doses of ethanolic and aqueous extracts of Crocus sativus following sciatic nerve chronic constriction injury (CCI) in rats. Amitriptyline (3, 10 and 30 mg/Kg, i.p.) and the extracts (25, 50 and 100 mg/Kg, i.p.), were separately administered at the time of CCI for 7 consecutive days. In combination therapy, the sub-antinociceptive dose of amitriptyline (3 mg/Kg) was given with the three different doses of extracts for seven days. Mechanical allodynia, thermal allodynia and thermal hyperalgesia were evaluated by von Frey, acetone and radiant heat tests, respectively, 1 day before and on days 3, 5 and 7 after surgery. Co-administration of amitriptyline (3 mg/Kg) with aqueous extract (50, 100 mg/Kg,) produced more potent cold anti-allodynic (P < 0.01 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects than that produced by each of them. Amitriptyline (3 mg/Kg) plus ethanolic extract (50, 100 mg/Kg) produced more potent cold anti-allodynic (P < 0.05 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects as compared with the sum effects produced by each of them. Mechanical anti-allodynia effect was only potentiated with the co-administration of amitriptyline with the high dose of aqueous extract (100 mg/Kg, P < 0.001). Our study supports the use of saffron as an adjunctive to amitriptyline to improve the therapeutic outcome in the management of neuropathic pain.

Alpha Lipoic Acid Plus Omega-3 Fatty Acids for Vestibulodynia Associated With Painful Bladder Syndrome.

This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS). Women with VBD/PBS were randomly assigned to receive amitriptyline or amitriptyline plus a commercially available preparation (ALAnerv Age; Alfa Wassermann, Bologna, Italy) containing, in 2 capsules, ALA 600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic acid 16.67 mg. Symptoms of burning and pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. Among 84 women who were randomized, the mean ± standard deviation dose of amitriptyline was 21.7 ± 6.6 mg/day, without statistical difference between the two groups. Pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly in both trial groups, with a greater effect seen with the addition of ALA and n-3 PUFAs. The addition of ALA/n-3 PUFAs to amitriptyline treatment was also associated with improvements in dyspareunia and pelvic floor muscle tone. The overall incidence of adverse events was low, and none led to treatment discontinuation. The addition of ALA/n-3 PUFAs to amitriptyline treatment in patients with VBD/PBS appears to improve outcomes and may allow for a lower dosage of amitriptyline, which may lead to fewer adverse effects.

Amitriptyline Dose and Treatment Outcomes in Specialty Headache Practice: A Retrospective Cohort Study.

To characterize treatment patterns and real world outcomes in headache patients treated with amitriptyline in an academic headache center. A retrospective chart review identified 178 patients in our center who were given a new prescription for amitriptyline in treatment of headache, and who were seen in follow-up within one year. Charts were reviewed to identify dosing patterns (initial and maximum dose) and persistence, patient-reported headache benefit, and reported side effects. Variables assessed in relation to medication use were comorbid psychiatric disease, headache characteristics, and prior use of a preventive medication. We followed patients for an average of 6.5 months. Initial and maximum prescribed amitriptyline doses were characterized as: "very low" (≤10 mg daily), "low" (11-25 mg daily), and "traditional" (≥25 mg daily). The initial dose of amitriptyline ranged from 2.5 to 50 mg daily, though most patients were started on a dose of 10 mg daily (112/178, 63%). Approximately 3/4 of the patients were found to have improvement (134/178) and 85% (129/151) were still taking amitriptyline at the last follow-up appointment. Maximum dosing ranged from 2.5 to 100 mg daily with most patients taking 10-25 mg (86/146, 58%). The most commonly reported adverse effect was daytime fatigue (17/151, 11%). There did not appear to be any effect from gender, ethnicity, race, diagnosis of sleep apnea, chronicity of migraine, presence of aura on our outcome measures. Our study supports the common clinical practice of using low doses of amitriptyline to treat chronic headache disorders and suggests that it was effective and well tolerated at doses lower than those used in many clinical trials. Use of low dosage amitriptyline may also improve medication persistence, an important clinical consideration in the management of this common and chronic condition. A subgroup of patients may experience a dramatic benefit from amitriptyline and this could warrant further investigation.

Prospective study of neuropathic pain after definitive surgery for extremity osteosarcoma in a pediatric population.

Neuropathic pain (NP) after definitive surgery for extremity osteosarcoma (OS) has not been previously characterized. This study prospectively investigates the incidence, duration, and treatment of NP in limb sparing surgery and amputation groups. In patients treated for OS on a chemotherapy and definitive surgery (limb sparing vs. amputation) protocol (OS08), we prospectively collected the following data: (i) demographical data (age, sex, race); (ii) NP time of onset and duration; and (iii) dose (starting, maximum) and duration of gabapentin, amitriptyline, and methadone treatment. Thirty-seven patients underwent 38 definitive surgeries: limb sparing (26, 68.4%) or amputations (12, 31.6%). Localization included lower extremity (30, 81%), upper extremity (6, 16%), or pelvis (1, 3%). Thirty patients (81%) developed NP and 26 of them required NP-specific medications (87.7%). The mean [standard deviation (SD)] duration of NP was 6.5 weeks (7.2) (median 4.4, range 0.3-29.9). All 26 patients (27 surgeries) treated with NP medications received gabapentin, either as single therapy (65.4%) (17 patients, 18 surgeries), dual therapy with gabapentin and amitriptyline (five patients), or triple therapy with gabapentin, amitriptyline, and methadone (four patients). The mean starting (maximum) doses of gabapentin, amitriptyline, and methadone (mg/kg/day) were 20.2 (43.8), 0.5 (0.7), and 0.3 (0.3), respectively. The incidence and duration of NP, duration of treatment, and NP-specific dose regimens were similar in the limb sparing and the amputation groups. NP after definitive surgery for OS is frequently encountered, can persist for a significant time, and NP outcomes are similar in limb sparing and amputation groups.

The effect of increasing amitriptyline doses on cardiomyocytes’ electrophysiology – simulation study

Abstract Background: Overdoses of tricyclic antidepressants may lead to arrhythmia. The aim of the study was to simulate the effect of increasing concentrations of amitriptyline (AMI) and its metabolite, nortriptyline, on the action potential of human ventricular cell. Methods: Simulations were performed in Cardiac Safety Simulator platform with the use of the O’Hara-Rudy model. Input data included literature-derived, drug-specific IC50 values for ICa(L), IKr, and INa currents. Individual concentrations of AMI and nortriptyline were simulated in Simcyp. Nine single doses (mg) were tested: 5, 10, 50, 100, 300, 500, 1000, 5000, and 10,000. Results: The values of simulated endpoints (APD50, APD90, triangulation, and ΔAPD90) increase with drug concentrations. ΔAPD90 was statistically significant for doses up from 1000 mg. EADs were observed after administration of 10,000-mg AMI. Conclusions: The consequences of various doses of AMI on the single cardiac myocytes were simulated in our study. Repolarization abnormalities were not expected for the therapeutic doses. EADs may be observed for very high doses of AMI.

Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs

ObjectiveTo evaluate the pharmacokinetics of amitriptyline and its active metabolite nortriptyline after intravenous (IV) and oral amitriptyline administration in healthy dogs. Study designProspective randomized experiment. AnimalsFive healthy Greyhound dogs (three males and two females) aged 2–4 years and weighing 32.5–39.7 kg. MethodsAfter jugular vein catheterization, dogs were administered a single oral or IV dose of amitriptyline (4 mg kg−1). Blood samples were collected at predetermined time points from baseline (0 hours) to 32 hours after administration and plasma concentrations of amitriptyline and nortriptyline were measured by liquid chromatography triple quadrupole mass spectrometry. Non-compartmental pharmacokinetic analyses were performed. ResultsOrally administered amitriptyline was well tolerated, but adverse effects were noted after IV administration. The mean maximum plasma concentration (CMAX) of amitriptyline was 27.4 ng mL−1 at 1 hour and its mean terminal half-life was 4.33 hours following oral amitriptyline. Bioavailability of oral amitriptyline was 6%. The mean CMAX of nortriptyline was 14.4 ng mL−1 at 2.05 hours and its mean terminal half-life was 6.20 hours following oral amitriptyline. Conclusions and clinical relevanceAmitriptyline at 4 mg kg−1 administered orally produced low amitriptyline and nortriptyline plasma concentrations. This brings into question whether the currently recommended oral dose of amitriptyline (1–4 mg kg−1) is appropriate in dogs.

Migraine in pregnancy.

Migraine is a predominantly female disorder. Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels and fluctuations. During pregnancy, estrogen may reach one hundred times the normal level, whilst progesterone levels decrease, rising again towards the end of the pregnancy; however, hormonal fluctuations are not as pronounced as during the non-pregnant state[1]. Most women with migraine report an improvement of their attacks during pregnancy, from the first to the third trimestre, particularly women with a history of menstrual migraine and with migraine without aura[2]. This improvement may be due to the lack of hormonal fluctuations but also to the increased levels of natural pain-killing hormones (endorphins) induced by pregnancy[1, 3]. If no improvement is seen toward the end of the first trimestre, migraine is likely to continue throughout pregnancy and postpartum. Most women with migraine improving in pregnancy will experience attack recurrence shortly after delivery, likely in the first weeks[2]. This decline might be due to the precipitous drop in estradiol and endorphin levels occurring in the postpartum period[1, 3]. A small number of pregnant women experience a worsening of their migraine while a few others may even develop de novo migraine symptoms. In this context, migraine usually occurs during the first trimestre and is most often with aura[2]. Women continuing to experience migraine attacks throughout pregnancy may require treatment but we need to consider that not all medications used for migraine are safe in pregnancy. Paracetamol is the preferred drug for acute treatment throughout pregnancy. If paracetamol is not sufficiently effective, sporadic use of sumatriptan can be considered. NSAIDs such as ibuprofen can also be used under certain circumstances, though their intake in the first and third trimestres is associated with specific risks and contraindications. For prevention, non pharmacological approaches are always first-line treatment, and should also be used to complement any drug treatment. Some vitamins and dietary supplements have been proposed, such as, magnesium, riboflavin and coenzyme Q10. Preventive drug treatment should only be considered in the most severe cases and should include low doses of β-blockers and amitriptyline[4]. A personal history of migraine headaches can affect pregnancy outcomes. There is increasing evidence showing that migraine is a risk factor for several vascular complications during pregnancy, including gestational hypertension and preeclampsia, stroke, myocardial infarction, and venous thromboembolism; therefore, migraine should be considered a potential cardiovascular risk factor in obstetric care[5]. Further research is warranted to understand the mechanisms underlying the increased risk of vascular disease in pregnant migraineurs. Better understanding of those mechanisms could lead to potential treatment and earlier intervention, thereby reducing the health care costs of morbidity and mortality associated with adverse vascular events in this population.

Mesaton (phenylephrine) Potentiates the Antidepressant and Eliminates the Sedative Action of Amitriptyline in Rats

Single i.m. doses of amitriptyline (10–30 mg/kg) induced a mild antidepressant effect in rats, decreasing immobility in the Porsolt test by factors of no more than 1.3–1.7. These doses of amitriptyline had significant sedative effects, as they decreased horizontal activity in the open field by factors of 3–6 and reduced vertical activity by factors of 2–2.5. Combined single i.m. administration of a low dose of amitriptyline (3 mg/kg) or a high dose of amitriptyline (30 mg/kg) combined with Mesaton (phenylephrine) at a threshold dose of 0.02 mg/kg (ineffective when given alone), induced a maximum antidepressant effect, decreasing immobility in the Porsolt test by factors of 3 and 4.6 respectively, but had no sedative side effect in the open field. The mechanism of potentiation of the antidepressant effect and elimination of the sedative effect of amitriptyline appears to be based on stimulation of gastric mucosal afferents by Mesaton.

Amitriptyline for fibromyalgia in adults.

This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of amitriptyline for neuropathic pain is now dealt with in a separate review. Amitriptyline is a tricyclic antidepressant that is widely used to treat fibromyalgia, and is recommended in many guidelines. It is usually used at doses below those at which the drugs act as antidepressants. To assess the analgesic efficacy of amitriptyline for relief of fibromyalgia, and the adverse events associated with its use in clinical trials. We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with reference lists of retrieved papers, previous systematic reviews and other reviews, and two clinical trial registries. We also used our own hand searched database for older studies. We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in fibromyalgia. We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. For efficacy, we calculated the number needed to treat to benefit (NNT), and for harm we calculated the number needed to treat to harm (NNH) for adverse events and withdrawals. We used a fixed-effect model for meta-analysis. We included seven studies from the earlier review and two new studies (nine studies, 649 participants) of 6 to 24 weeks' duration, enrolling between 22 and 208 participants; none had 50 or more participants in each treatment arm. Two studies used a cross-over design. The daily dose of amitriptyline was 25 mg to 50 mg, and some studies had an initial titration period. There was no first or second tier evidence for amitriptyline in the treatment of fibromyalgia. Using third tier evidence the risk ratio (RR) for at least 50% pain relief, or equivalent, with amitriptyline compared with placebo was 3.0 (95% confidence interval (CI) 1.7 to 4.9), with an NNT) of 4.1 (2.9 to 6.7) (very low quality evidence). There were no consistent differences between amitriptyline and placebo or other active comparators for relief of symptoms such as fatigue, poor sleep, quality of life, or tender points. More participants experienced at least one adverse event with amitriptyline (78%) than with placebo (47%). The RR was 1.5 (1.3 to 1.8) and the NNH was 3.3 (2.5 to 4.9). Adverse event and all-cause withdrawals were not different, but lack of efficacy withdrawals were more common with placebo (12% versus 5%; RR 0.42 (0.19 to 0.95)) (very low quality evidence). Amitriptyline has been a first-line treatment for fibromyalgia for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against years of successful treatment in many patients with fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline will be one option in the treatment of fibromyalgia, while recognising that only a minority of patients will achieve satisfactory pain relief. It is unlikely that any large randomised trials of amitriptyline will be conducted in fibromyalgia to establish efficacy statistically, or measure the size of the effect.

Pharmacological Evaluation of Antidepressant-Like Effect of Genistein and Its Combination with Amitriptyline: An Acute and Chronic Study.

The present study was designed to evaluate the acute and chronic antidepressant effect of genistein in combination with amitriptyline in mice. Animals were divided into six groups (n = 6) for treatment with water, genistein, or amitriptyline, either alone or in combination for ten days. Animals were subjected to locomotor activity testing; tail suspension test (TST); and forced swim test (FST) and immobility time was recorded on day one and day ten. Acute treatment of all treatment groups did not significantly reduce the immobility time (p > 0.05). Chronic treatment of combination of genistein (10 mg/kg) and amitriptyline (5 mg/kg and 10 mg/kg) significantly reduced the immobility time as compared to control group (p < 0.001) and was comparable to amitriptyline alone (10 mg/kg). However, no changes in anti-immobility activity in combination of subeffective doses of genistein (5 mg/kg) and amitriptyline (5 mg/kg) were observed. Genistein at its standard dose (10 mg/kg) rendered synergistic effects in combination with subeffective dose of amitriptyline (5 mg/kg) and additive effects in combination with therapeutic dose of amitriptyline (10 mg/kg).

Establishment and characterization of an optimized mouse model of multiple sclerosis-induced neuropathic pain using behavioral, pharmacologic, histologic and immunohistochemical methods

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes debilitating central neuropathic pain in many patients. Although mouse models of experimental autoimmune encephalomyelitis (EAE) have provided insight on the pathobiology of MS-induced neuropathic pain, concurrent severe motor impairments confound quantitative assessment of pain behaviors over the disease course. To address this issue, we have established and characterized an optimized EAE-mouse model of MS-induced neuropathic pain. Briefly, C57BL/6 mice were immunized with MOG35–55 (200μg) and adjuvants comprising Quil A (45μg) and pertussis toxin (2×250ng). The traditionally used Freund's Complete Adjuvant (FCA) was replaced with Quil A, as FCA itself induces CNS neuroinflammation. Herein, EAE-mice exhibited a mild relapsing–remitting clinical disease course with temporal development of mechanical allodynia in the bilateral hindpaws. Mechanical allodynia was fully developed by 28–30days post-immunization (p.i.) and was maintained until study completion (52–60days p.i.), in the absence of confounding motor deficits. Single bolus doses of amitriptyline (1–7mg/kg), gabapentin (10–50mg/kg) and morphine (0.1–2mg/kg) evoked dose-dependent analgesia in the bilateral hindpaws of EAE-mice; the corresponding ED50s were 1.5, 20 and 1mg/kg respectively. At day 39 p.i. in EAE-mice exhibiting mechanical allodynia in the hindpaws, there was marked demyelination and gliosis in the brain and lumbar spinal cord, mirroring these pathobiologic hallmark features of MS in humans. Our optimized EAE-mouse model of MS-associated neuropathic pain will be invaluable for future investigation of the pathobiology of MS-induced neuropathic pain and for efficacy profiling of novel molecules as potential new analgesics for improved relief of this condition.

The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice.

There is a close relationship between chronic stress, glucocorticoids and depression. Psychiatric and cognitive symptoms resembling major depression have been observed in patients experiencing elevated glucocorticoid levels, and a high percentage of people suffering from depression have undergone a stressful event/events prior to the onset of this mental disorder. In our study, we investigated whether acute and chronic treatment of dexamethasone induces depression-like behavior in mice and if dexamethasone therapy influences the activity of antidepressant drugs with diverse modes of action. The antidepressant-like effect was assessed by the forced swim test in adult mice. The depressogenic-like activity of dexamethasone turned out to be dose-dependent: only the highest tested dose of the glucocorticoid (i.e., 64μg/kg) given as a single injection increased immobility time, whereas 16μg/kg/day of dexamethasone (but not 4μg/kg/day) administered repeatedly induced a significant alteration in animal behavior. These depressogenic doses of dexamethasone (i.e., 64μg/kg and 16μg/kg/day for an acute and repeated administration, respectively) diminished the antidepressant potential of the therapeutic doses of imipramine (10mg/kg), amitriptyline (10mg/kg), tianeptine (25mg/kg), mianserin (10mg/kg), citalopram (15mg/kg) and moclobemide (25mg/kg). Two main findings of our study should be particularly underlined: (1) both single and repeated administration of dexamethasone evoked a depression-like behavior of mice, (2) both single and repeated administration of dexamethasone were able to modify the activity of the antidepressant agents from various pharmacological groups, which may lead to a considerable reduction in the efficacy of pharmacotherapy prescribed for patients with mood disorders.

Parsonage-Turner Syndrome Initially Suspected of Being Orthopedic Diseases in a Primary Care Setting: A Case Report

Parsonage-Turner syndrome (PTS), also known as neuralgic amyotrophy or brachial neuritis, consists of a complex set of symptoms including sudden onset shoulder pain, usually unilaterally, followed by progressive neurologic deficits such as motor weakness, dysesthesia and numbness. We report a case of a 45-year-old Japanese man with PTS, who was initially suspected of having orthopedic diseases, such as cervical spondylosis and suprascapular nerve entrapment syndrome. The patient presented with acute-onset severe pain in his right arm and neck, followed by muscle weakness. We diagnosed PTS by taking a detailed medical history, ruling out other differential diagnoses, and by considering the characteristic clinical symptoms and the denervation pattern identified by needle electromyography. High-dose corticosteroid therapy prednisolone (PSL) relieved the initial sharp pain and oral amitriptyline successfully relieved the residual nighttime pain. Doses of PSL and amitriptyline were tapered, pain was alleviated, and the patient returned to full-time work after discharge in one-and-a-half years. For prompt diagnosis, physicians should consider the possibility of PTS in patients with acute onset of severe arm pain or subsequent muscle weakness and muscle atrophy in the arm or shoulder girdle. J Med Cases. 2014;5(4):197-201 doi: http://dx.doi.org/10.14740/jmc1696w

The effects of acute treatment with paroxetine, amitriptyline, and placebo on the equilibrium function in healthy subjects: A double-blind crossover trial

Objective. Depression is common in old age, and is treatable with antidepressants. However, antidepressants use can increase the risk of falls. Thus, we assessed the effects of antidepressants on equilibrium function using posturography. Methods. This study recruited 10 healthy male volunteers (35.3 ± 3.7 years). In this double-blinded, three-way crossover trial, they received acute doses of 10 mg paroxetine, 25 mg amitriptyline, and placebo. They were administered posturography at baseline and 4-h postdosing. Results. At 4-h postdosing, amitriptyline significantly decreased the locus length per unit area (L/A) and increased the envelope area compared with those at baseline. Meanwhile, the total length and the locus length per time (L/T) at 4-h postdosing of amitriptyline did not show significant differences from those at baseline. After paroxetine treatment, there were no significant differences in total length, L/T, L/A, and the envelope area between baseline and 4-h postdosing. Conclusion. An acute dose of amitriptyline significantly decreased L/A and increased the envelope area as markers of body sway. Evaluation of equilibrium function is important for preventing the potential risk of falls and body sway after taking antidepressants.

Optimization and characterization of a rat model of prostate cancer-induced bone pain using behavioral, pharmacological, radiological, histological and immunohistochemical methods

The major limitation of currently utilized rodent models of prostate cancer (PCa)-induced bone pain (PCIBP) involving intra-osseous injection of PCa cells, is their relatively short-term applicability due to progressive deterioration of animal health necessitating euthanasia. Here, we describe establishment of an optimized rat model of PCIBP where good animal health was maintained for at least 90-days following unilateral intra-tibial injection (ITI) of PCa cells. We have characterized this model using behavioral, pharmacological, radiological, histological and immunohistochemical methods. Our findings show that following unilateral ITI of 4×104 AT3B PCa cells (APCCs), there was temporal development of bilateral hindpaw hypersensitivity that was fully developed between days 14 and 21 post-ITI. Although there was apparent spontaneous reversal of bilateral hindpaw sensitivity that was maintained until at least day 90 post-ITI, administration of bolus doses of the opioid receptor antagonist, naloxone, rescued the pain phenotype in these animals. Hence, upregulation of endogenous opioid signaling mechanisms appears to underpin apparent spontaneous resolution of hindpaw hypersensitivity. Importantly, the histological and radiological assessments confirmed that tumor formation and development of osteosclerotic metastases was confined to the APCC-injected tibial bones. In our rat model of PCIBP, single bolus doses of morphine, gabapentin, meloxicam and amitriptyline produced dose-dependent relief of mechanical allodynia and thermal hyperalgesia in the bilateral hindpaws. The optimized rat model of PCIBP characterized herein has potential to provide new insights into the pathophysiological mechanisms associated with long-term (mal)adaptive pain due to advanced PCa-induced bony metastases and for screening novel compounds with potential for improved alleviation of this condition.

The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test

The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 μg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.

14A. Pelvic Pain and Headache in an Adolescent Female: A Case of Self-determination and Healthful Recovery

Focus Areas: Integrative Approaches to Care, Pediatrics, Alleviating PainA 16-year-old previously healthy white female presented to our office with complaints of a 1-year history of chronic severe pelvic pain, leg pain, and severe daily headaches that were adversely affecting her school performance. Her leg and pelvic pain caused weakness and discomfort to the point that she used a walker or a wheelchair when she had to ambulate distances longer than 20 feet. She had been disenrolled from school where she had been an honor student. She had seen several specialists in areas including gynecology, neurology, pain management, and pelvic floor physical therapy. Extensive laboratory workup, including testing for Lyme disease, was negative. Exploratory laparoscopy did not elucidate any significant pelvic pathology. Medical management with appropriate doses of non-steroidal antiinflammatory medication, amitriptyline, lyrica, oral contraceptives, and Depo-Provera did not provide any significant relief. Through a series of visits to our office, it was determined that she was incredibly motivated to return to school but was having significant difficulty managing her advanced school work due to severe headaches and trouble with concentration. She denied any specific triggering factor for her symptoms and did not have a mood disorder. With behavior-modification recommendations, she worked independently on increasing her daily activities and has been able to rehabilitate to the point that she no longer uses a walker or a wheelchair to move around. This case demonstrates the potential that a therapeutic relationship can have for facilitating patient recovery. The importance of open communication with the patient and family, addressing their concerns, and seeking a source and treatment regimen outside of a paradigm of a psychosocial trauma were highlighted by this process.

Amitriptyline versus placebo for major depressive disorder.

Amitriptyline is a tricyclic antidepressant that was synthesised in 1960 and introduced as early as 1961 in the USA, but is still regularly used. It has also been frequently used as an active comparator in trials on newer antidepressants and can therefore be called a 'benchmark' antidepressant. However, its efficacy and safety compared to placebo in the treatment of major depression has not been assessed in a systematic review and meta-analysis. To assess the effects of amitriptyline compared to placebo or no treatment for major depressive disorder in adults. We searched the Cochrane Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR-Studies and CCDANCTR-References) to August 2012. This register contains relevant randomised controlled trials from: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). The reference lists of reports of all included studies were screened and manufacturers of amitriptyline contacted for details of additional studies. All randomised controlled trials (RCTs) comparing amitriptyline with placebo or no treatment in patients with major depressive disorder as diagnosed by operationalised criteria. Two review authors independently extracted data. For dichotomous data, we calculated the odds ratio (OR) with 95% confidence intervals (CI). We analysed continuous data using standardised mean differences (with 95% CI). We used a random-effects model throughout. The review includes 39 trials with a total of 3509 participants. Study duration ranged between three and 12 weeks. Amitriptyline was significantly more effective than placebo in achieving acute response (18 RCTs, n = 1987, OR 2.67, 95% CI 2.21 to 3.23). Significantly fewer participants allocated to amitriptyline than to placebo withdrew from trials due to inefficacy of treatment (19 RCTs, n = 2017, OR 0.20, 95% CI 0.14 to 0.28), but more amitriptyline-treated participants withdrew due to side effects (19 RCTs, n = 2174, OR 4.15, 95% CI 2.71 to 6.35). Amitriptyline also caused more anticholinergic side effects, tachycardia, dizziness, nervousness, sedation, tremor, dyspepsia, sedation, sexual dysfunction and weight gain. In subgroup and meta-regression analyses the results of the primary outcome were robust towards publication year (1971 to 1997), mean participant age at baseline, mean amitriptyline dose, study duration in weeks, pharmaceutical sponsor, inpatient versus outpatient setting and two-arm versus three-arm design. However, higher severity at baseline was associated with higher superiority of amitriptyline (P = 0.02), while higher responder rates in the placebo groups were associated with lower superiority of amitriptyline (P = 0.05). The results of the primary outcome were rather homogeneous, reflecting comparability of the trials. However, methods of randomisation, allocation concealment and blinding were usually poorly reported. Not all studies used intention-to-treat analyses and in many of them standard deviations were not reported and often had to be imputed. Funnel plots suggested a possible publication bias, but the trim and fill method did not change the overall effect size much (seven adjusted studies, OR 2.64, 95% CI 2.24 to 3.10). Amitriptyline is an efficacious antidepressant drug. It is, however, also associated with a number of side effects. Degree of placebo response and severity of depression at baseline may moderate drug-placebo efficacy differences.

Therapeutic Drug Monitoring of Antidepressants in Haemodialysis Patients

The co-morbidity of depressive disorder and chronic kidney failure is remarkably common. However, knowledge about the influence of haemodialysis on the serum concentration of antidepressants is sparse. In this study we examined the influence of haemodialysis on the serum concentrations of the antidepressants amitriptyline (and its active metabolite nortriptyline) and mirtazapine. The authors retrospectively evaluated therapeutic drug monitoring (TDM)-analyses obtained in eight different regional medical dialysis centres before and after haemodialysis and compared serum concentrations of amitriptyline and mirtazapine using t-tests. Mean serum concentrations of the sum of amitriptyline + nortriptyline (before: 75.52 ng/mL; after: 59.35 ng/mL; p < 0.001) and mirtazapine (before: 53.45 ng/mL; after: 38.31 ng/mL; p < 0.036) decreased significantly with haemodialysis. Haemodialysis patients received rather low doses of amitriptyline (mean 36.5 mg; SD 17.6; range 10-75 mg) and mirtazapine (mean 24.7 mg; SD 9.1; range 15-45 mg). For haemodialysis patients with depression an adequate antidepressant drug dosage must be administered. TDM is necessary in order to optimize antidepressant therapy in patients with chronic kidney disease.