Antioxidants Supplementation in Acute Amitriptyline Abuse for Pain.

The fundamental aim of this study is to establish the role of antioxidant supplementation in alleviating acute amitriptyline induced oxidative stress. The effect of supplementation was compared on treatment of acute amitriptyline intoxication cases for pain management, with alpha lipoic acid (ALA) alone or with vitamin C, with that of healthy individuals (group I), and those receiving only routine standard treatment (RST) as control (group II). A total of 132 human subjects divided into 5 groups were supplemented with either placebo, RST, RST with vitamin C, RST with ALA, or RST with vitamin C, and ALA. Results of this study revealed that the decrease in the level of oxidative stress and enzyme activity was observed among those supplemented with either alpha lipoic acid alone or along with vitamin C, with a slightly more decrease in the latter group. P value of < 0.001 was considered statistically significant. The percentage of benefit of treatment on supplementation with vitamin C and alpha lipoic acid showed a marked increase in group V cases after supplementation with both in combination. The results provided that the oxidative stress induced by acute amitriptyline poisoning is comparatively decreased by supplementation with antioxidants like alpha lipoic acid and vitamin C, than those only on routine standard treatment.

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice.

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.

Compounded Topical Analgesics for Chronic Pain.

Analgesic medications compounded for topical use are gaining popularity for the management of chronic pain. The advantages of topical pain medications include reduction of systemic adverse effects, improved patient acceptance, few drug interactions, ease of dose determination, avoidance of first-pass metabolism, and direct access to the target site. Compounded topical medications typically use a mixture of 3 or more single medications to achieve multiple complementary effects at lower doses of each individual medication. Herein, we review the mechanisms, adverse effects, and evidence for some of the most commonly used medications in topical compounds for pain management. Because more topical medications are used for chronic pain, dermatologists can expect an increase in irritant and allergic contact dermatitis related to these medications.

Dalitong granule combined with electroacupuncture in the treatment of functional dyspepsia: A randomized controlled trial.

OBJECTIVE: To explore clinical short and long-term effect of combining dalitong granule (DG) and electroacupuncture group (EA) in the treatment of functional dyspepsia. METHODS: Totally 640 patients with confirmed functional dyspepsia were randomly divided into 4 groups using a randomized digital table: the DG group, the EA group, the combined group and the control group, 160 cases in each group. The DG group was treated with 6 g DG 3 times daily; the EA group was treated with puncture of points Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6), Taichong (LR3) and Gongsun (SP4) twice daily; the combined group with above-mentioned DG and EA; and the control group with 5 mg mosapride 3 times, 20 mg pantoprazole and 25 mg amitriptylines twice daily. The treatment course was 4 weeks for all groups. The symptom score, quality of life score by Short Form 36 Health Survey Questionnaires (SF-36), plasma motilin by radioimmunoassay, electrogastrographic frequencies by electrogastrogram (EGG) and gastric emptying by B-sonography were examined, and adverse reactions were observed before, at the end of treatment and 60 weeks post-treatment. RESULTS: In the DG group 1 case dropped out for not taking medicine strictly and 1 case was lost to follow-up, while 1 case in the EA group and 2 cases in the combined therapy group were lost to follow-up. Compared with pre-treatment, quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all increased significantly, while symptom score was decreased significantly at the end of treatment in each group (P<0.01); in the combined group quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all significantly higher than those in the other groups, while symptom score was significantly lower than in the other groups (P<0.05). Compared with at the end of treatment, these indices changed insignificantly in the combined group and the EA group 60 weeks post-treatment (P>0.05), but the 4 increased indices were all decreased significantly, and symptom score was increased significantly in the DG and the control groups (P>0.05). The short and long-term total effective rates in the combined group were all significantly higher than those in the other treatment groups (P<0.05 or P<0.01). No serious adverse reaction occurred in the four groups. CONCLUSION: Combined treatment of DG and EA could increase both plasma motilin and electrogastrographic frequencies, promote gastric emptying, alleviate the symptom of dyspepsia so as to increase quality of life, with better safety and long-term effect.

Topical treatment in pain medicine: from ancient remedies to modern usage.

Over several millennia, substances have been applied to the skin for treatment of pain. Some ingredients are in current use; others have been discontinued. Mechanisms of action include interactions with nociceptive neural networks and inflammatory processes. Substances must penetrate the stratum corneum barrier and vehicles that enhance penetration have been developed. Topical drugs with links to the past include menthol, capsaicin, some opioids, local anesthetic agents and NSAIDs. Mandragora is also described as an example of a herbal remedy that has been discontinued due to its toxicity. The future for topical drugs is promising, with the advent of new drugs tailored for specific pain mechanisms and the development of both penetration enhancers and sterile preparation methods.

Berberine Ameliorates Allodynia Induced by Chronic Constriction Injury of the Sciatic Nerve in Rats.

The objective of this study was to investigate whether berberine could ameliorate allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats. After inducement of CCI, significant increases in the number of paw lifts from a cold plate test (cold allodynia) and decreased paw withdrawal threshold in the von Frey hair stimulation test (mechanical allodynia) were observed. However, these cold and mechanical allodynia were markedly alleviated by berberine administration in a dose-dependent manner. Sciatic nerve myeloperoxidase and malondialdehyde activities were also attenuated by berberine administration. Continuous injection for 7 days induced no development of tolerance. The antiallodynic effect of 20 mg/kg berberine was comparable to that of amitriptyline 10 mg/kg. This study demonstrated that berberine could mitigate allodynia induced by CCI, a neuropathic pain model, and it suggested that the anti-inflammatory and antioxidative properties of berberine contributed to the antiallodynic effect in the CCI model.

[Therapeuetic aspects of cluster headache in the practical clinical site].

The therapeutic procedures of cluster headache begin from the precise diagnose. Because cluster headache is usually accompanied with teeth pain and/or neck pain, some patients aren't able to consult adequate medical institutions. In this lecture I showed the some male and female patients as examples. The female patient was suffered from menstruation related migraine in her period of cluster headache. From the view point of treatment, preventive medicines are essential. They not just reduce severity and also improve the length of headache-period. Suitable preventive medicines may avoid the whole severe attacks. We reported therapeutic experiences of valproate, gabapentin and amitriptyline with verapamil in 2010 at general meeting of Societas Neurologica Japonica. Steroids are not indispensable. As for triptans rapid-type one are usually used. If the attacks are severe, sumatriptan subcutaneous injection kit (SSI) needs to be introduced. The expert nurses who are skilled in the procedures of SSI improve both patients' adherence and therapeutic efficiency. We held a first educational meeting of SSI in Tokyo 2012. Because cluster headache is formidable, the integrated therapy which is composed of precise diagnosis, preventive medicine and adequate medicines for headache attacks is essential and needed.

Displaced dual-mode imaging with desorption electrospray ionization for simultaneous mass spectrometry imaging in both polarities and with several scan modes.

Displaced dual-mode imaging (DDI) is introduced as a method for simultaneous imaging in positive and negative-ion mode on the same sample with desorption electrospray ionization imaging, as well as a method for simultaneous imaging in full-scan and tandem mass spectrometry (MS/MS) mode. DDI is performed by using a smaller row distance in the y-direction than the desired image resolution and recording for example every second row in positive-ion mode and the other half of the rows in negative-ion mode, thus resulting in two separate images. This causes some degree of oversampling, which is thus utilized to obtain complementary mass spectrometric of the sample. Imaging with both polarities is exemplified on an imprint of a Hypericum perforatum leaf containing secondary metabolites which ionize in both polarites and a mouse kidney containing phospholipids which ionize in positive or negative mode only. Simultaneous full-scan and MS/MS imaging was demonstrated on the same mouse kidney, as the mouse had been given a relatively low dose of the antidepressive drug amitriptyline. While the full-scan data allowed imaging of the endogenous phospholipids, the drug and its metabolites were only visible in the MS/MS images. The latter approach is useful, for example in whole-body imaging experiments where the full-scan data gives an overview of the tissue, and the MS/MS mode provides the sensitivity to image trace amounts of drugs and metabolites.

An assessment of the in vivo effects of intravenous lipid emulsion on blood drug concentration and haemodynamics following oro-gastric amitriptyline overdose.

BACKGROUND: Overdose with lipophilic drugs, such as amitriptyline, may cause cardiotoxicity in overdose. Severe poisoning can be resistant to traditional treatments. Intravenous lipid emulsion (ILE) has been recommended as a novel therapy for the treatment of such overdoses; however, a little is known about the effects of ILE-infusion on drug concentration and haemodynamics in the early/absorptive phase after oral poisoning. METHOD: Thirty minutes after oro-gastric administration of amitriptyline (70 mg/kg), either 20% intravenous lipid emulsion (ILE), 8.4% sodium bicarbonate or Hartmann's solution was infused to anaesthetized and ventilated rodents (n = 10 per group). Heart rate, blood pressure, cutaneous ECG - QRS interval duration (QRS-d), and survival were serially recorded over 120 min. Blood drug concentrations were also collected during this period. Continuous variables were compared using one-way ANOVA. RESULTS: ILE infusion significantly decreased the survival compared to other treatments (10% ILE vs 70% bicarbonate vs 70% Hartmann's solution, p = 0.005). There was a gradual prolongation of QRS-d and fall in blood pressure over time compared to baseline (T0) measurement for both ILE and Hartmann's solution treatments. This was associated with significantly increased blood AMI concentration with ILE treatment at T60, T90 and T120 min to the other treatments (p < 0.02). CONCLUSION: Administration of ILE early after oral amitriptyline overdose resulted in worse survival and no improvement in haemodynamics. In addition, blood amitriptyline concentrations were higher in the ILE-treated group. This suggests that either drug absorption from the gastrointestinal-tract was facilitated or drug redistribution was retarded when ILE was given early after oral poisoning.

Oral treatment with amitriptyline induces coenzyme Q deficiency and oxidative stress in psychiatric patients.

Amitriptyline is a commonly prescribed tricyclic antidepressant, which has been shown to impair mitochondrial function and increase oxidative stress in a variety of in vitro assays. Coenzyme Q(10) (CoQ(10)), an essential component of the mitochondrial respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In order to evaluate the putative mitochondrial toxicity of amitriptyline, we have analyzed CoQ(10) and ATP levels, oxidative damage and mitochondrial mass in peripheral blood cells from control healthy volunteers and psychiatric patients with depressive episodes treated or non-treated with amitriptyline. In patients not following amitriptyline treatment, CoQ(10) and ATP levels and mitochondrial mass were reduced when compared to normal individuals while lipid peroxidation was clearly increased. All these alterations were aggravated in patients following oral amitriptyline therapy. These results suggest that mitochondrial dysfunction could be involved in the pathophysiology of depression and may be worsened by amitriptyline treatment. CoQ(10) supplementation is postulated to counteract the adverse effects of amitriptyline treatment in psychiatric patients.

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. METHODS: Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. RESULTS: Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. CONCLUSION: Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

[Long-term psychiatric consequences of carbon monoxide poisoning: a case report and literature review]. / Intoxication au monoxyde de carbone: quelles séquelles neuropsychiatriques? A propos d'un cas clinique et revue de la littérature.

Carbon monoxide intoxication (COI) can result in severe neuropsychiatric lesions that are however granted little attention in literature. Following the description of affective and neurological symptoms in a 37-year-old female patient five years following COI, we will review, across the literature (Medline 1974--2006), the long-term neuropsychiatric consequences, etiopathogenic hypotheses, prognoses and treatments to apply. Subjective symptoms are reported by the quasi-totality of patients for over more than 30 years following COI. More than half of patients are diagnosed as suffering from cognitive impairments and other neurological symptoms after years following COI. Affective disorders are observed in almost three-fourths of patients and personality disorders in more than half. Numerous cerebral lesions and perfusion disorders can be observed through IRM, PET scan and SPECT and related to the clinical symptomatology of the patient. COI may constitute a risk factor in the waking of long-term neuropsychiatric disorders in a context of environmental and neurobiological complex factor interaction. A close follow-up must be envisaged with neuropsychiatric assessments and regular neuroimagery in order to adapt at best therapeutic interventions to the patient's clinical status. First and foremost prevention and education remain the key solution to the reduction of morbidity and mortality of COI.

Diagnosing and managing migraine headache.

Headache is one of the chief complaints among patients visiting primary care physicians. Diagnosis begins with exclusion of secondary causes for headache. More than 90% of patients will have a primary-type headache, so diagnosis can often be completed without further testing. Although tension-type headaches are the most common kind of headache, patients with this type of headache rarely seek treatment unless occurrence is daily. Migraine, which affects more than 30 million people in the United States, is the most common headache diagnosis for which patients seek treatment. Migraine is a chronic, often inherited condition involving brain hypersensitivity and a lowered threshold for trigeminal-vascular activation. Intermittent debilitating attacks are characterized by autonomic, gastrointestinal, and neurologic symptoms. Migraine results in a marked decrease in a patient's quality of life, as measured by physical, mental, and social health-related instruments. Accurate assessment of a patient's disability will guide physicians in prescribing appropriate modes of therapy. However, migraine remains underdiagnosed, and patients with migraine remain undertreated. A comprehensive treatment approach to migraine may include nonpharmacologic measures, as well as abortive and prophylactic medications. Informing patients about realistic treatment expectations, possible delayed efficacy of medications, and avoidance of caffeine and overuse of medications is critical for successful outcomes. Management of migraine is a dynamic process, because headaches evolve over time and medication tachyphylaxis may occur, necessitating changes in therapy. Pathologic findings in the neck constitute an accepted etiology or precipitant for headache. Osteopathic manipulative treatment may reduce pain input into the trigeminal nucleus caudalis, favorably altering neuromuscular-autonomic regulatory mechanisms to reduce discomfort from headache.

The guinea pig forced swim test as a new behavioral despair model to characterize potential antidepressants.

RATIONALE: Behavioral despair is a model of high predictivity for antidepressant activity in murids. For some drug targets, guinea pigs exhibit a higher homology to their human counterparts compared to murids. OBJECTIVES: In this paper, we established a model of behavioral despair namely, the forced swim test (FST) in guinea pigs. MATERIALS AND METHODS: Male guinea pigs underwent the FST similar to rats. Animals received intraperitoneal injections of either vehicle or drugs 24, 4, and 0.5 h before testing. We tested the tricyclic antidepressants desipramine and amitriptyline, the monoamine oxidase inhibitor tranylcypromine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, and the neurokinin 1 (NK(1)) receptor antagonist, L-733,060, and for comparison the antipsychotic clozapine and the stimulant methamphetamine. RESULTS: Desipramine (> or =3 mg/kg) and amitriptyline (>10 mg/kg) increased the latency to immobility (LTI) to greater than 230 s, and tranylcypromine (10 mg/kg) it to greater than 190 s. Paroxetine (>0.3 mg/kg) and fluoxetine (>10 mg/kg) also increased LTI significantly but only to greater than 120 s. Methamphetamine (3 mg/kg) completely eliminated immobility, whereas clozapine (5-20 mg/kg) had no effect. L-733,060 (10 mg/kg) increased LTI to 270 s. Doses producing significant effects in FST were investigated in the open field. Antidepressants did not affect locomotion, whereas methamphetamine induced hyperlocomotion. CONCLUSIONS: We demonstrate the suitability of a modified procedure of the FST for a nonmurid species: the guinea pig. Known antidepressants showed similar effects as in rats and mice. It is interesting to note that the NK(1) antagonist L-733,060 increased forced swimming, suggesting its antidepressant potential. Thus, the guinea pig FST allows the study of antidepressant activity also in NK(1) antagonists that cannot be studied appropriately in murids.

Pharmacological treatment compared to behavioural treatment for juvenile tension-type headache: results at two-year follow-up.

Recurrent headaches are common in children and adolescents. Most current investigations have employed limited modalities (either medication or behavioural) and few have included comparisons of different treatments. In this study relaxation training, administered in a limited contact format, and amitriptyline were compared for juvenile episodic tension-type headache. The clinical improvement was significant for both groups at 1- and 2-year follow-up; in particular for behavioural treatment, the patients came regularly for the sessions, practised routinely, and appeared to be compliant and accepting of treatment, although we did not assess this formally. In this group of patients the percentage of drop-outs was lower than in the pharmacological tratment. Although clinical results were similar in both groups, relaxation therapy seems to be more accepted than medication. The limited contact modality seems to be as useful as other behavioural approaches that require a greater investment of time (by patients and therapists), without unpleasant side effects. Because the sample sizes are small, these conclusions are tentative.

Sham device v inert pill: randomised controlled trial of two placebo treatments.

OBJECTIVE: To investigate whether a sham device (a validated sham acupuncture needle) has a greater placebo effect than an inert pill in patients with persistent arm pain. DESIGN: A single blind randomised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls. Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study. SETTING: Academic medical centre. PARTICIPANTS: 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored > or =3 on a 10 point pain scale. INTERVENTIONS: Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks. MAIN OUTCOME MEASURES: Arm pain measured on a 10 point pain scale. Secondary outcomes were symptoms measured by the Levine symptom severity scale, function measured by Pransky's upper extremity function scale, and grip strength. RESULTS: Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups, but changes were not different between the groups (-0.14, 95% confidence interval -0.52 to 0.25, P = 0.49). Changes in severity scores for arm symptoms and grip strength were similar between groups, but arm function improved more in the placebo pill group (2.0, 0.06 to 3.92, P = 0.04). Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group (-0.33 (-0.40 to -0.26) v -0.15 (-0.21 to -0.09), P = 0.0001) and on the symptom severity scale (-0.07 (-0.09 to -0.05) v -0.05 (-0.06 to -0.03), P = 0.02). Differences were not significant, however, on the function scale or for grip strength. Reported adverse effects were different in the two groups. CONCLUSIONS: The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in. Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals.

Amitriptyline neurotoxicity: dose-related pathology after topical application to rat sciatic nerve.

BACKGROUND: Amitriptyline is a tricyclic antidepressant drug used systemically for the management of neuropathic pain. Antidepressants, as a class of drugs with direct neurologic actions, are becoming widely used for the management of chronic pain, although their mechanisms are not entirely understood. Amitriptyline exerts potent effects on reuptake of norepinephrine and serotonin and blocks alpha 2A adrenoreceptors and N-methyl-D-aspartate receptors. Because amitriptyline is also a particularly potent blocker of sodium channels and voltage-gated potassium and calcium channels, it has been recommended as a long-acting local anesthetic agent. Unfortunately, amitriptyline has significant toxic side effects in the central nervous system and cardiovascular system that are dose-related to its systemic administration. Therefore, before amitriptyline can be used clinically as a local anesthetic agent, it should be thoroughly explored with respect to its direct neurotoxic effect in the peripheral nervous system. METHODS: The left sciatic nerve of Sprague-Dawley rats (12/ group) received a single topical amitriptyline dose of 0.625, 1.25, 2.5, or 5 mg; a saline group (n = 2) was used as control. Neuropathologic evaluations were conducted in separate animals (n = 4) 1, 3, and 7 days later. RESULTS: Amitriptyline topically applied in vivo to rat sciatic nerve causes a dose-related neurotoxic effect. Drug doses of 0.625-5 mg all caused Wallerian degeneration of peripheral nerve fibers, with the number of affected fibers and the severity of the injury directly related to the dose. CONCLUSION: Because the effective local anesthetic dose is within this dose range, the authors strongly recommend that amitriptyline not be used as a local anesthetic agent.

Prognostic factors of postherpetic neuralgia.

The investigation was aimed to determine prognostic factors related to postherpetic neuralgia (PHN), and treatment options for preventing PHN. The data showed 34 (17.0%) out of 188 patients with herpes zoster had severe pain after 4 weeks, and 22 (11.7%) after 8 weeks, compared with 109 (58.0%) at presentation. The age (>/=50 yr), surface area involved (>/=9%), and duration of severe pain (>/=4 weeks) might be the main factors that lead to PHN. On the other hand, gender, dermatomal distribution, accompanied systemic conditions, and interval between initial pain and initiation of treatment might not be implicated in PHN. The subjects were orally received antiviral (valacyclovir), tricyclic antidepressant (amitriptyline), and analgesic (ibuprofen) as the standard treatment in the group 1. In addition to the standard medication, lidocaine solution was sub- and/or perilesionally injected in the group 2, while lidocaine plus prilocaine cream was topically applied to the skin lesions in the group 3. The rates of PHN in the 3 treatment groups were not significantly different, suggesting adjuvant anesthetics may not be helpful to reduce the severity of pain.