Gabapentin Withdrawal Syndrome in a Post–Liver Transplant Patient

ABSTRACT

A 41-year-old male with a previous orthotopic liver transplant began experiencing insomnia, anxiety, diaphoresis, headaches, and palpitations that progressed over a 2-day period. As part of his home medication regimen, the patient was taking gabapentin for peripheral neuropathy. His acute onset of increasing symptoms coincided with an inadvertent discontinuation of gabapentin. After reinitiation of gabapentin therapy, the symptoms slowly improved over the next 24 hours and the episode of gabapentin withdrawal syndrome resolved.     

Ranolazine-related dyspnea on exertion

Background: Ranolazine is increasingly being prescribed for the treatment of chronic stable angina. This report describes an adverse effect that may be related to ranolazine.Case summary: A 77-year-old white man with chronic renal insufficiency was evaluated for moderate dyspnea on exertion (DOE). Cardiac and pulmonary workup revealed nonobstructive coronary artery disease and mild obstructive lung disease. The patient had been taking ranolazine 500 mg daily for possible angina for the past 2 months. Given the temporal association of his symptoms with drug initiation, ranolazine was discontinued during the hospitalization. One month after discontinuing ranolazine, the patient's DOE had completely resolved; the only intervention had been discontinuation of ranolazine. The patient's Naranjo algorithm score was 3, indicating a possible adverse drug reaction.Conclusions: No previous cases of ranolazine-related DOE requiring drug cessation have been published. Ranolazine may be associated with DOE in this elderly man.     

Methimazole-induced cholestatic jaundice in an elderly hyperthyroid patient

Background: Hyperthyroidism is a common disease in the elderly. Antithyroid medications such as methimazole are one of the few treatment options.Case summary: A 76-year-old white woman presented to the clinic with a 1-week history of fatigue, sleepiness, 7-pound weight loss, and tachycardia. Her blood work showed low levels of thyroid-stimulating hormone and high levels of free thyroxine. Due to persistence of her symptoms, she was hospitalized and started on methimazole 10 mg TID. Six weeks after receiving methimazole for the treatment of hyperthyroidism, she had severe jaundice and itching. Results of her liver function tests showed elevation of her alkaline phosphatase and liver transaminase levels, as well as hyperbilirubinemia, formed mainly of the conjugated fraction. Methimazole-induced cholestatic jaundice was diagnosed. Her symptoms gradually improved after discontinuation of the medication, and plasma bilirubin levels were near normal after 8 weeks without methimazole.Conclusions: We report here a probable association between methimazole use and severe cholestatic jaundice in an elderly hyperthyroid patient. The patient's jaundice was reversed after drug discontinuation. (Am J Geriatr Pharmacother. 2007;5:236-240).     

Probable levetiracetam-associated depression in the elderly: Two case reports

Background: Compared with traditional antiepileptic drugs, levetiracetam has a unique mechanism of action and unique properties, including predominant renal excretion and lack of drug-drug interactions. In the elderly, depression associated with levetiracetam has not been reported.Case summaries: A 73-year-old black man (height, 172.7 cm; weight, 92.7 kg; body mass index [BMI], 31 kg/m²) with stage 4 kidney disease was taking levetiracetam 500 mg BID for partial complex seizures. After 5 months of taking medication, new-onset depression, evidenced by depressed mood, weight loss, fatigue, and appearing withdrawn, was noted in this patient. Levetiracetam was discontinued by order of the patient's primary care physician. At a follow-up appointment 4 weeks later, the depressive symptoms had nearly resolved. The patient's Naranjo Adverse Drug Reaction Probability Scale score was 6, indicating levetiracetam to be a probable cause of depression in this patient. In a second case, a 92-year-old white woman (height, 154.9 cm; weight, 54.5 kg; BMI, 22.7 kg/m²) with existing chronic kidney disease and new-onset partial seizure, likely due to a meningioma, was initiated on levetiracetam 500 mg once daily. Depressive symptoms (eg, anhedonia, hypersomnolence, decreased appetite) were noted within 5 weeks. Cessation led to improvement in mood and cognition within 8 days. Based on this patient's Naranjo Adverse Drug Reaction Probability Scale score of 6, levetiracetam was a probable cause of depression in this patient.Conclusions: Levetiracetam was a probable cause of depression in these 2 elderly patients. Cautious use and additional monitoring may be necessary when prescribing levetiracetam to elderly patients, especially when prescribing to those with a history of renal impairment.     

Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: A randomized-sequence,double-blind,placebo-controlled crossover study in healthy volunteers

Background: Gabapentin enacarbil is an actively transported prodrug of gabapentin that provides predictable dose-proportional gabapentin exposure with high (≥68%) oral bioavailability.Objectives: The aims of this study were to investigate the pharmacokinetics and tolerability of gabapentin enacarbil up to supratherapeutic doses and the effects of gabapentin enacarbil on cardiac repolarization in healthy volunteers, and to provide a dose reference for a future definitive QT/corrected QT (QTc) study.Methods: This was a randomized-sequence, double-blind, placebo-controlled, single escalating-dose, crossover study of gabapentin enacarbil 600-mg extended-release tablets administered as a single oral dose of 2400, 3600, 4800, or 6000 mg or placebo, with a 1-week washout between administrations. Blood samples were collected over a period of 36 hours after administration and were analyzed using a validated method of liquid chromatography/tandem mass spec-trometry. Blood gabapentin enacarbil and gabapentin concentrations were analyzed using noncompartmental methods. Tolerability was assessed by monitoring adverse events (AEs) (using subject interview/reporting), laboratory parameters, vital sign measurements, and 12-lead electrocardiography (ECG). Holter ECG was also performed.Results: Thirty-two healthy volunteers were included in the study (18 women, 14 men; mean [SD] age, 31.2 [11.4] years; body mass index, 24.9 [3.04] kg/m²). Gabapentin enacarbil was converted rapidly to gaba-pentin after absorption. Gabapentin exposure in blood was proportional to gabapentin enacarbil dose over the range of 2400 to 6000 mg (1250–3125 mg-equivalent gabapentin). Blood concentrations of intact gabapen-tin enacarbil were low and transient (≤0.5% of the released gabapentin concentration at all doses). The most commonly reported AEs were dizziness and nausea (50% and 25% of subjects, respectively). All but 4 AEs were mild to moderate in intensity. Two subjects experienced treatment-emergent AEs rated as severe: psychomotor retardation, vertigo, and sedation (4800-mg dose) and somnolence (6000 mg). All treatment-emergent AEs resolved without medical intervention. No serious AEs were reported, and none of the AEs led to study withdrawal. There were no clinically significant changes in laboratory parameters, vital sign measurements, or ECG values; QTc intervals did not exceed 480 msec or change from baseline >30 msec at any gabapentin enacarbil dose.Conclusions: Gabapentin enacarbil was associated with dose-proportional gabapentin exposure at doses up to 6000 mg and was generally well tolerated in these healthy subjects. These findings support the use of 6000-mg gabapentin enacarbil in a definitive QT/QTc study.     

Selective serotonin reuptake inhibitor discontinuation syndrome in children: Six case reports

Background: Antidepressant discontinuation syndrome refers to a cluster of symptoms that occur after abrupt dose reduction or discontinuation of antidepressant medication. Selective serotonin reuptake inhibitors (SSRIs) are increasingly being used for the treatment of depression and other psychiatric disorders in children and adolescents, but published data on SSRI discontinuation syndrome in children are limited.Objective: This paper presents 6 case reports of SSRI discontinuation syndrome in children.Results: SSRI discontinuation syndrome was diagnosed in 6 patients (4 boys, 2 girls; mean age, 11.33 ± 1.75 years) according to established criteria. Three patients had been taking paroxetine, 2 fluvoxamine, and 1 sertraline for an average of 4.00 ± 1.67 months (range, 3-6 months) before abrupt discontinuation or dose reduction. Dizziness/lightheadedness/drowsiness, poor concentration, nausea, headache, and fatigue were the most frequent symptoms. As in previous studies in adults, the 6 patients experienced SSRI discontinuation symptoms 1 to 5 days (mean 2.92 ± 1.63 days) after SSRI discontinuation or dose reduction. In all patients, symptoms resolved on reinitiation of treatment with the same SSRI or a different one.Conclusions: The case reports presented in this article suggest that SSRI discontinuation syndrome can and does occur in children when treatment is stopped or the SSRI dose is reduced abruptly, and is quite similar to that reported in adults. Placebo-controlled prospective studies are needed in children to further assess the prevalence and clinical presentation of SSRI discontinuation syndrome and to develop management strategies for this condition.     

A probable case of gabapentin-related reversible hearing loss in a patient with acute renal failure

BACKGROUND: As described in the literature, gabapentin toxicity in patients with impaired renal function can manifest as coma, myoclonus, tremulousness, or altered mental status. Gabapentin is an antiepileptic agent indicated for use as an adjunct therapy in partial seizures and postherpetic neuralgia but is also prescribed for the treatment of diabetic peripheral neuropathy. CASE SUMMARY: A 46-year-old white woman (height, 167 cm; weight, 177 kg; body mass index, 62.8 kg/m2) with a 6-year history of diabetes mellitus and previously normal renal function, presented to the emergency department of Wake Forest University Baptist Medical Center with anuria (a serum creatinine level of 7.4 mg/dL), hearing loss, myoclonus, and confusion with hallucinations lasting for 3 days. Her blood pressure was 110/74 mm Hg. The patient's preadmit medication list included: lisinopril (40 mg QD), hydrochlorothiazide (25 mg QD), and furosemide (80 mg QD) for hypertension; atorvastatin (10 mg QD) for hyperlipidemia; omeprazole (20 mg QD) for gastroesophageal reflux disease; salmeterol/fluticasone inhaler (100/50 microg; 1 puff BID) and albuterol metered-dose inhaler (90 microg as needed) for asthma; metformin (500 mg BID) and insulin lispro per sliding scale for type 2 diabetes mellitus; oxycodone controlled release (60 mg TID) for chronic osteoarthritis and low back pain; alprazolam (0.5 mg every 8 hours as needed) for generalized anxiety disorder; venlafaxine (150 mg BID) for depression; and gabapentin (300 mg TID) for diabetic peripheral neuropathy. The patient's symptoms (hearing loss, myoclonus, and confusion) improved after 1 session of hemodialysis (approximately 10 hours following admission) and had resolved at the time of discharge (4 days later). On admission, the gabapentin concentration was 17.6 microg/mL, and following hemodialysis, the gabapentin concentration was undetectable (by discharge/day 4). The timing of the patient's last dose of gabapentin is unknown. Normal doses for the treatment of diabetic peripheral neuropathy range from 900 to 3600 mg/d divided 3 times daily. Conclusions: We report a patient with acute renal failure who developed hearing loss, myoclonus, and confusion with hallucinations in the presence of elevated gabapentin concentrations. Due to rapid improvement after hemodialysis and discontinuation of gabapentin, we believe that these symptoms were probably due to gabapentin toxicity.     

The Role of Anxiety Sensitivity in Eating Pathology

Background  In past research, anxiety sensitivity (AS) has been identified as a risk factor for anxiety, mood, and alcohol problems. Little work, however, has examined the relationship between AS and eating pathology. We predicted that individuals high in AS would have elevated rates of eating disorder symptoms as measured by the Eating Disorder Inventory (EDI). Methods  Participants in two studies—one undergraduate sample (N = 88) and one clinical sample (N = 96)—were assessed for anxiety sensitivity and eating disorder symptoms. Results  In both samples, AS was significantly related to EDI-Bulimia scores, controlling for depressive symptoms, trait anxiety symptoms, and impulsivity. In the clinical sample, AS was also significantly related to EDI-Drive for Thinness, controlling for the same covariates. A follow-up analysis suggested that the relationship between AS and EDI eating disorder symptoms was mediated by EDI-Interoceptive Awareness. Limitations  Both studies were cross-sectional, which prohibits causal interpretations. The follow-up mediational analysis must be interpreted with caution due to overlap between the measures of AS and interoceptive awareness. Because of a small sample size and significant comorbidity, the exploratory results analyzing diagnostic categories in Study 2 must be interpreted with caution. Conclusions  AS has a statistically significant relationship to certain eating disorder symptoms measured by the EDI. Future research should investigate whether high AS individuals utilize certain eating behaviors in an effort to regulate somatic symptoms of anxiety.

Sydenham’s Chorea

BackgroundSydenham's chorea is the most common acquired movement disorder of adolescence. This clinical manifestation of acute rheumatic fever has a clear and documented relationship with Group A streptococcal infections. The symptoms are involuntary choreiform movements that can affect the face and all extremities. The pathophysiology remains unclear.Case ReportA 12-year-old female was brought to the emergency department with a 2-week history of involuntary muscle spasms of her right arm and leg. Her parents reported intermittent slurred speech and difficulty grasping utensils. Physical examination revealed an awake, alert, age-appropriate female with normal cranial nerves. Patient was found to have choreoathetoid movements on the right extremities with dystonia of right leg with ambulation. Neurology consultation, computed tomography of the head, and magnetic resonance imaging of the brain did not show any acute pathology. Echocardiogram did show mild tricuspid regurgitation, suggestive of rheumatic fever. Anti-streptolysin O titer was markedly elevated, along with DNAse-B antibodies. The patient had marked improvement of movement disorder at just over 1 week later.Why Should An Emergency Physician Be Aware of This?Sydenham's chorea is a rare but important movement disorder often related to Group A streptococcus and rheumatic fever. The incidence of rheumatic fever has been decreasing in North America but continues to be much more prevalent in developing countries as well as immigrant populations. This diagnosis is rare and can occasionally be misdiagnosed as a “fidgety” child or as a psychiatric manifestation. Sydenham's chorea is important to diagnose because acute treatment and prophylactic antibiotics can help improve symptoms and minimize cardiac damage.     

Behavioral changes with paranoia in an elderly woman taking atorvastatin

Background: There have been a number of published reports of central nervous system (CNS) adverse effects with statins.Case summary: A 79-year-old woman developed paranoia, anxiety, and behavioral changes ~2.5 weeks after starting atorvastatin 10 mg/d. The patient had no other medication changes at this time. After 2 months of therapy, the patient discontinued atorvastatin, and her symptoms fully resolved after 4 days.Conclusions: This is the first case report, to our knowledge, describing paranoia as one of the symptoms associated with statin therapy. Our report suggests an adverse reaction due to the initiation of atorvastatin via the temporal relationship between the start of atorvastatin and symptom onset, as well as termination of therapy and subsequent symptom disappearance. Use of the Naranjo adverse drug reaction probability scale to assess causality revealed a “probable” association (score, 5) for this adverse event. This report emphasizes the possibility of paranoia as a CNS adverse effect due to statin therapy. Statins are frequently used in older populations and should therefore be considered when such CNS adverse effects occur during therapy.     

Experiential Avoidance in Individuals with Hoarding Disorder

Hoarding disorder (HD) has received increased research attention. A cognitive-behavioral model implicates dysfunctional beliefs about possessions in these problems. Although this model has received growing support, other perspectives are needed. A recent investigation in an undergraduate sample reported that experiential avoidance (EA) predicted hoarding symptoms above and beyond hoarding-specific beliefs. The present study attempted to replicate and extend those findings in a clinical sample. We compared individuals meeting diagnostic criteria for HD (N = 33) to matched healthy controls (N = 30), as well as other anxiety disorders (N = 32). Results revealed that the HD group experienced less EA compared to individuals with other anxiety disorders. Compared to healthy control individuals, those with HD experienced heightened EA, but this difference was attributable to group differences in the symptoms of depression, anxiety and stress. Within the HD group, EA was not related to any domain of hoarding symptoms. In contrast, beliefs about possessions predicted hoarding behaviors (particularly excessive acquisition and difficulty discarding) above and beyond general distress. Implications for the role of EA in HD are discussed.     

Gabapentin for treatment of behavioral and psychological symptoms of dementia

OBJECTIVE: To report the use of gabapentin in the treatment of behavioral and psychological symptoms of dementia (BPSD) and to review the available literature relating to the use of gabapentin in this population. CASE SUMMARY: A 62-year-old white man was admitted to the hospital due to a worsening state of confusion, anxiety, depressed mood, insomnia, and verbal and physical aggressiveness toward his wife. He had a past medical history significant for vascular dementia. He had been intolerant of or had failed to respond to numerous antidepressants, benzodiazepines, and neuroleptics. The addition of gabapentin to the patient's medication regimen resulted in reduced agitation, sexual inappropriateness, and lability. He was discharged to his home on a dose of gabapentin 300 mg three times daily. DATA SOURCES: A MEDLINE search (1966-August 2000) was performed to identify case reports and clinical trials discussing the efficacy of gabapentin in the treatment of BPSD. DISCUSSION: Gabapentin, like other anticonvulsants, has been used with success in several psychiatric illnesses. Available literature indicates that the drug may have some efficacy in the treatment of BPSD. It has a favorable adverse effect profile in the elderly, which makes it an attractive altemative to standard therapies, including benzodiazepines and neuroleptics. Optimal dosing remains unclear. CONCLUSIONS: This case suggests that gabapentin is a reasonable alternative therapy for patients whose behavioral symptoms do not respond to conventional agents.     

Effects of pitavastatin on cerebral blood flow

Background: Hypercholesterolemia has been identified as an important risk factor for stroke. It has been reported that statins might reduce the risk for new or recurrent cardiovascular events and strokes.Objective: This paper reports on the effects of pitavastatin on cerebral blood flow in 2 elderly patients.Case summary: Two patients, a 72-year-old right-handed Japanese man and a 77-year-old right-handed Japanese woman, both with a history of cerebral infarction, received 6-month treatment with pitavastatin 2 mg/d for complicated hypercholesterolemia. To assess regional cerebral blood flow (rCBF), single-photon emission computed tomography (SPECT) studies with technetium-99m-ethyl cysteinate dimer were carried out before and after pitavastatin administration. Tomography was evaluated using the Easy z Score Imaging System. None of the patients' other treatments, with the exception of pitavastatin initiation, were modified during the treatment period. In both patients, serum total cholesterol concentrations were improved within 3 months of initiation of pitavastatin treatment, with no marked changes in clinical symptoms. In both patients, improvement was found in rCBF on SPECT. The z score of the left parietal lobe in 1 patient was improved, from 2.20 to 1.69. That of the other patient was also improved, from 2.42 to 1.94.Conclusion: In both patients, clinically significant improvement in rCBF was found after 6-month treatment with pitavastatin 2 mg/d.     

Psychotic symptoms during phenibut (beta-phenyl-gamma-aminobutyric acid) withdrawal

Background: Phenibut is a GABAB agonist that was developed in the Soviet Union in the 1960s. In Russia, it is used in clinical practice to treat, for example, anxiety and alcohol withdrawal symptoms. In Europe and in the United States, phenibut is marketed as a nutritional supplement for improved sleep. In different Internet discussion forums, there are several reports of withdrawal symptoms. Aim: Our aim was to share what we have learnt from a case study wherein a patient was followed throughout the whole abstinence period.

Case report: A somatically healthy man in his mid-20s with a previous history of substance abuse took phenibut for 2 months. He noted tolerance development already after the first week and increased doses up to 20 g/day. Already a few hours after the last dose the patient started to experience subjective symptoms, at the third day of abstinence the patient started to hallucinate and the following day’s symptoms were aggravated with increased hallucinations and confusion. After treatment with benzodiazepines the psychosis resolved.

Conclusion: Phenibut withdrawal symptoms can become severe and have similarities to Baclofen, GHB, benzodiazepine and alcohol withdrawal. Benzodiazepines and supportive care seems to be the most effective choice of treatment for objective abstinence symptoms.     

Allergic interstitial nephritis possibly related to sunitinib use

Background: Sunitinib is an oral multitargeted inhibitor indicated for the treatment of renal cell carcinoma.Objective: This report describes a case of allergic interstitial nephritis possibly related to this agent.Case Summary: A 69-year-old female patient with a history of metastatic renal cell carcinoma after left radical nephrectomy presented to our nephrology clinic after completing 2 courses of sunitinib therapy. The patient was noted to have progressive kidney dysfunction with proteinuria, together with peripheral eosinophilia and eosinophiluria, which developed during the first of 2 cycles of sunitinib therapy. Her concomitant medications included atenolol, triamterene/hydrochlorothiazide, amlodipine, and multivitamin tablets, all of which she had been receiving at stable doses over the previous 2 years. There were no other over-the-counter medications involved and other possible causes of interstitial nephritis were excluded. The proteinuria, eosinophilia, and eosinophiluria worsened with the second course and resolved after sunitinib discontinuation, which resulted in initial stabilization followed by slight improvement in kidney function. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 7, indicating a probable association of the event with the drug. With clinical improvement after discontinuation of sunitinib and the presence of a solitary remaining kidney and thrombocytopenia, renal biopsy was not performed after discussion with the patient. When challenged with a related agent, sorafenib, the patient experienced worsening of serum creatinine and increasing eosinophilia, similar to that noted with sunitinib, suggesting that this event may be a class effect.Conclusions: Nephrologists and oncologists should be aware of allergic interstitial nephritis as an adverse effect related to this agent. Although there are no current recommendations for monitoring serum creatinine with sunitinib therapy, we recommend that serum creatinine and white cell count with differential be checked within 2 weeks of initiation of therapy with sunitinib to enable earlier diagnosis of this condition and avoid renal damage.     

The Ruminative Response Style in Adolescents: An Examination of Its Specific Link to Symptoms of Depression

This study further examined the relation between a ruminative response style and symptoms of depression in nonclinical adolescents aged 12–18 years (N = 231). Participants completed questionnaires that measure rumination, neuroticism, and symptoms of depression and anxiety. Results indicated that rumination was significantly linked to symptoms of depression, and that this link remained significant when controlling for neuroticism. However, when concurrent anxiety symptoms were also taken into account, rumination was no longer significantly related to symptoms of depression. Interestingly, rumination appeared to be a significant correlate of anxiety symptoms, even after controlling for neuroticism and concurrent symptoms of depression. Support was found for a mediation model in which the link between neuroticism and depression and anxiety symptoms was partially mediated by rumination.

小舞蹈病的临床特点及误诊原因分析

目的:分析小舞蹈病的临床特点,以提高对小舞蹈病的认识,减少临床误诊。方法:对2005年1月-2007年7月年收治的3例小舞蹈病患者的临床资料、临床诊断及误诊原因进行分析。结果:3例中,起病前有急性扁桃体感染史1例;所有病例均有肢体的不自主运动和肌张力低下,其中伴有面部症状2例,小脑症状1例,精神症状2例;抗链球菌溶血素O增高2例。超声心动图检查发现心脏异常1例,表现为二尖瓣稍增厚伴中度二尖瓣反流、主动脉瓣稍增厚伴轻度主动脉瓣反流。3例颅脑核磁共振成像均正常。3例中仅1例获及时诊断,其余2例均有不同程度的误诊。经青霉素、氟哌啶醇等药物治疗后患者症状均有明显改善。结论:小舞蹈病患者缺乏特征性临床表现,易被临床误诊。