By R. Marius. Molloy College.

A direct comparison of FDG PET and HMPAO-SPECT in their ability to differentiate AD from vascular dementia indicated higher diagnostic accuracy for PET regardless of dementia severity (98) buy generic lyrica 75 mg on line. Using ROC curves buy generic lyrica 150mg line, PET diagnostic accuracy was better than SPECT for an MMSE score greater than 20 (87 cheap lyrica 150 mg line. Other studies confirmed a lower sensitivity for even high-resolution SPECT compared with PET (99) purchase 75 mg lyrica mastercard. Moreover, the parietal hypoperfusion observed using SPECT in patients with AD has been observed in such other conditions as normal aging, vascular dementia, posthypoxic dementia, and sleep apnea (100). Functional Magnetic Resonance Imaging Two studies combined APOE genotyping and fMRI in per- sons at riskof AD. Bookheimer and associates (101) per- formed fMRI studies while 30 cognitively intact middle- aged and older persons (mean age, 63 years) memorized and retrieved unrelated word pairs. Statistical parametric maps of recall versus control did not differ significantly from the 14 persons without blocks for APOE-4 carriers and noncarriers. Maps were standard- ized into a common coordinate system. Both groups showed sig- APOE-4 in age, prior educational achievement, or rates of nificant MRI signal intensity increases in frontal, temporal, and AD family history. Brain activation patterns were deter- parietal regions, and the APOE-4 group had greater extent and mined during both learning and retrieval taskperiods and intensity of activation. The APOE-4 group showed additional acti- vations in the left parahippocampal region, left dorsal prefrontal were analyzed using between-group and within-subject ap- cortex, and other regions in the inferior and superior parietal proaches. Memory performance was reassessed on 12 sub- lobes, and anterior cingulate. N Engl J Med 2000;343:450–456, with significantly greater magnitude and spatial extent of MRI permission. This pattern of activation was greater in the left hemisphere, consistent with the verbal creased activation patterns could result from subclinical nature of the task, and during the retrieval rather than the neuropathology in the inferotemporal region or in the in- learning condition. Longitudinal data indicated that greater puts to that region. The greater signal in persons Longitudinal Studies of Glucose with the APOE-4 genetic risksuggests that the brain may Metabolism of Persons At Risk of recruit additional neurons to compensate for subtle deficits. Dementia Moreover, the longitudinal data are encouraging that fMRI may be a useful approach to prediction of future cognitive Both the University of California, Los Angeles (UCLA) and decline and early AD detection. At UCLA, a total of 20 nondemented subjects persons at riskfor AD, visual naming and letter fluency (ten APOE-4 carriers and ten without APOE-4) received tasks were used to activate brain areas involved in object repeat PET and neuropsychologic testing 2 years after base- and face recognition during fMRI scanning (102). Subjects line assessment (mean SD for follow-up was 27. The ten APOE-4 carriers available for longi- with AD and one APOE-4 allele. The low-riskgroup was tudinal study were similar to the ten noncarriers in matched for age, education, and cognitive performance. Memory performance scores did not differ signifi- Chapter 86: Structural and Functional Brain Imaging of Alzheimer Disease 1239 AD because of age or genetic riskor both have now been confirmed at two centers in separate subject cohorts. To- gether, these studies indicate that combining PET imaging of glucose metabolism and genetic riskmay be useful out- come markers in AD prevention trials. Functional brain imaging techniques could be used to trackpreclinical cogni- tive decline and to test candidate prevention therapies with- out having to perform prolonged multisite studies using FIGURE 86. Regions showing the greatest metabolic decline incipient AD as the primary outcome measure. The consis- after 2 years of longitudinal follow-up in nondemented patients tency and extent of the metabolic decline in these well- with APOE-4 (SPM analysis) included the right lateral temporal and inferior parietal cortex (brain on the left side of the figure). Cerebral decline pattern was noted in subjects without APOE-4 such metabolic and cognitive decline in persons at genetic risk for Alz- that larger groups per treatment arm would be needed. Proc Natl Acad Sci USA 2000; 343:450–456, with These observations provide an opportunity for presymp- permission. Until now, such trials involved studies of preclinical subjects with more severe memory impairments consistent with MCI, wherein approximately 50% of subjects actually develop dementia cantly according to genetic riskeither at baseline or follow- over a 3- to 4-year period. The MCI trials have required up, and the APOE-4 carriers and noncarriers did not differ hundreds of subjects for adequate power. These trials use significantly in cognitive change after 2 years. The introduction of FDG PET imaging showed significant glucose metabolic decline (4%) in the combined with APOE-4 genetic riskincreases efficiency and left posterior cingulate region in APOE-4 carriers. The SPM reduces costs by addressing the research questions with analysis showed significant metabolic decline in the inferior fewer subjects. Our group is currently performing two such parietal and lateral temporal cortices with the greatest mag- placebo-controlled trials, one using the cyclooxygenase-2 nitude (5%) of metabolic decline in the temporal cortex inhibitor celecoxib and the other using the cholinesterase (Fig. After correction for multiple comparisons, this inhibitor donepezil. Based on these data from only ten subjects, the estimated Cost Benefit and Cost Effectiveness power of PET under the most conservative circumstances Using neuroimaging as a surrogate marker early in the dis- is 0. Such findings suggest that com- benefits beyond the greater efficiency in preclinical trials. The homogeneity in clinical trials of mild to moderate AD. University of Arizona group also found that APOE-4 het- Rather than treating the conventional clinical syndrome of erozygotes had significant 2-year declines in regional brain AD, the refined phenotype would include a specific neu- activity, the largest of which was in temporal cortex, and roimaging pattern (e. If PET can improve diagnostic accuracy, particularly in APOE-4 noncarriers. Their findings suggest that as few as in the preclinical and early disease stages, then patients 22 cognitively normal, middle-aged APOE-4 heterozygotes would be treated earlier, with resulting improvements in would be needed in each treatment arm (i. When uncertain and placebo) to test a prevention therapy over a 2-year pe- about diagnosis, clinicians generally perform costly repeti- riod (103). The greater accuracy of early AD detec- tion that neuroimaging may offer would facilitate early in- tervention. Offsetting the pharmacy costs would be the cost Clinical Trials of Presymptomatic savings from avoidance of repetitive and unnecessary exami- Patients Using Neuroimaging Surrogate nations. Following evidence from placebo-controlled stud- Markers ies, the assessment of economic impact would be another The longitudinal findings of significant parietal and tem- level of analysis driving decision makers to fund new neu- poral metabolic decline in asymptomatic persons at riskof roimaging technologies. Definitive diagnosis and treatment 1240 Neuropsychopharmacology: The Fifth Generation of Progress during presymptomatic stages of AD would likely decrease coherence and neuropsychological tests in dementia. The improved diagnostic ac- troencephalogr 1995;26:47–58. An introduction and overview of clinical applica- curacy could improve efficacy in clinical trials and could tions of NeuroSPECT in psychiatry. J Clin Psychiatry 1992; thus facilitate early optimal treatment, delay further cogni- 53[Suppl]:3–6. Positron emission tomography stud- the highest-quality care. Positron emission tomography and autoradiography: principles and applications for the brain and heart. The use of positron emission tomography in the clinical assessment of dementia. This workis supported in part by the following: the Alzhei- Semin Nucl Med 1992;22:233–246. Clin Positron Imaging Research, Los Angeles; and National Institutes of Health 1999;2:119–130. Assessment of cognitive deficit models, and clinical examples. Ann NY Acad Sci 1987;508: in geriatric patients: a study of physician behavior. Neurology 1997;49: men: the Honolulu-Asia Aging Study. Localization of brain function Mazziotta JC, Gilman S, eds. Clinical brain imaging: principles and applications. J Neurosci longitudinal CT studies of ventricular change. MR procedures and biomedi- bases of two fundamental memory processes in the human me- cal implants, materials, and devices: 1993 update. Arch Gen Psychiatry 1987;44: event-related fMRI study. Reduced EEG remembering and forgetting of verbal experiences as predicted coherence in dementia: state or trait marker? Relationships between EEG blood flow and oxidative metabolism during somatosensory Chapter 86: Structural and Functional Brain Imaging of Alzheimer Disease 1241 stimulation in human subjects. Report of a National Institute of Mental Health 83:1140–1144. Estimated prevalence of age-associated accompanying sensory stimulation: functional brain mapping memory impairment derived from standardized tests of memory with magnetic resonance imaging. Brain regions pairment: clinical characterization and outcome. Arch Neurol associated with episodic retrieval in normal aging and Alzhei- 1999;56:303–308.

Neuroimaging in the developmental disorders: the reading disability in boys and girls: results of the Connecticut state of the science cheap lyrica 150 mg on-line. Exceptional LD profile orale: a systematic 75mg lyrica mastercard, quantitative review of its structural buy lyrica 75mg without prescription, func- types for the WISC-III and WIAT order lyrica 75 mg on-line. School Psychol Rev 1999; tional and clinical significance. A magnetic reso- profiles of reading disability: comparisons of discrepancy and nance imaging study of planum temporale asymmetry in men low achievement definitions. A functional neuroim- of individual differences in the acquisition of literacy. Read Res aging description of two deep dyslexic patients. Normal planum temporale asymmetry in and the discrepancy model for children with learning disabili- dyslexics with a magnocellular pathway deficit. Brain activity in visual of difficult-to-remediate and readily remediated poor readers: cortex predicts individual differences in reading performance. Washington, DC: American Psychological analysis for identifying instructional components needed to im- Association, 1994. Does phoneme awareness training in ing and attention disorders: separate but equal. Pediatr Clin kindergarten make a difference in early word recognition and North Am 1999;46:885–897. What ness: a study with inner-city kindergarten children. Ann Dyslexia reading research tells us about children with diverse learning needs. Effects of instruction on the decoding skills of chil- 16. Alternative diagnostic approaches dren with phonological processing problems. J Learn Disabil for specific developmental reading disabilities. The development of reading- reading: a meta-analysis of experimental training studies. Individual differences in response to early inter- 19. The nature of phonological process- ventions in reading: the lingering problem of treatment resisters. Development of phono- 610 Neuropsychopharmacology: The Fifth Generation of Progress logical and orthographic skill: a 2-year longitudinal study of 65. Repeated reading to enhance fluency: Psychol Rev 1993;22:27–48. Decoding, reading, and reading dis- chiatry 1963;120:458–464. Preventing read- mine on children: studies on subjects with learning disabilities ing failure in young children with phonological processing dis- and school behavior problems. Arch Gen Psychiatry 1967;17: abilities: group and individual responses to instruction. Effects of reading compre- idate on paired-associate learning and porteous maze perfor- hension interventions for students with learning disabilities. Dextroampheta- hension: a synthesis of research in learning disabilities. In: mine sulfate in children with learning disorders: effects on per- Scruggs TE, Mastropieri MA, eds. Advances in learning and ception, learning, and achievement. Arch Gen Psychiatry 1969; behavioral disabilities, vol 10. Seattle: Special for learning disabled students: a review of the research. Psychotropic drugs and learning problem: a selec- 50. Review of stimulant drugs in learning and behav- for curriculum. Methylphenidate in matical word problems for students with learning disabilities: hyperactive children: differential effects of dose on academic, a meta-analysis. Psychostimulant effects on learning education classrooms. Writing and self-regulation: with attention deficit hyperactivity disorder. Clin Psychol Rev cases from the self-regulated strategy development model. Psychostimulant effects on learning ers: From teaching to self-reflective practice. New York: Guilford, and cognitive function: findings and implications for children 1998:20–41. Strategy instruction in planning: teaching students 1995;15:1–32. Treatment of hand- of methylphenidate on the cognitive, learning and academic writing problems in beginning writers: from handwriting to performance of children with attention deficit disorder in the composition. Composing via dictation and speech recognition sys- 27:191–211. Teaching students with learning and behavior nual Meeting of the International Neuropsychological Society problems. Dextroam- tools for students with learning disabilities: a comparison of phetamine: its cognitive and behavioral effects in normal and strategies to increase text entry speed. Learn Disabil Res Pract hyperactive boys and normal men. Curriculum-based measurement: the emerging alter- 81. Combining performance assessment and amine: suggestions for attention deficit-hyperactivity disorder. Monitoring basic skills progress sional complexity of multi-channel EEG indicates change of [Computer programs]. Nootropic drugs have different effects (DYX3) for dyslexia is located on chromosome 2. J Med Genet on kindling-induced learning deficits in rats. Behavior on chromosome 6p influences different aspects of develop- disorders in rats exposed to intrauterine hypoxia, and their cor- mental dyslexia. Reading disability: evidence for a genetic Med 1993;115:43–45. Psychopharmacology (Berl) 1976;49: for specific language and reading deficits on chromosome 6p. Piracetam as an aid to learning of reading and mathematics performance: a twin study. Psychopharmacology (Berl) 1979; Genet Med Gemellol 1992;41:287–300. Effects of piracetam in children ics and reading deficits: evidence for a genetic etiology. Etiology of covariation between read- ing and mathematics performance: a twin study. J Clin Psychopharmacol 1985;5: confirmation of qualitative analyses. J Child Psychol Psychiatry writing disorders in dyslexic children. Piracetam and dys- temporo-parietal white matter as a basis for reading ability: evi- lexia: effects on reading tests. J Clin Psychopharmacol 1987;7: dence from diffusion tensor magnetic resonance imaging [see 230–237. Dynamics of blood event-related potentials in dyslexic males. Int J Psychophysiol flow velocity in middle cerebral arteries in dyslexic persons. Developmental upon visual event-related potentials in dyslexic children. Psycho- dyslexia and attention dysfunction in adults: brain potential physiology 1987;24:513–521. Neuroreport children with developmental reading disorder (Report to UCB, 1999;10:3459–3465. A functional lesion ton, DC: George Washington University Medical School De- in developmental dyslexia: left angular gyral blood flow predicts partment of Psychiatry, 1987. Dissociation of tam in two subgroups of students with dyslexia enrolled in normal feature analysis and deficient processing of letter-strings summer tutoring. A controlled study of Tourette mal cerebellar activation with motor learning difficulties in dys- syndrome. Attention-deficit disorder, learning disorders, and lexic adults. A controlled family history study of in reading-disabled twins.

These results show that rats will in alcohol vapor chambers 75mg lyrica free shipping. Rats then were tested in the operant boxes with access maintain and sustain lever pressing for alcohol during de- to 10% alcohol and water across two 12-hour periods separated pendence if the animals have a history of lever pressing for by 4 days of vapor exposure cheap 75mg lyrica otc. A third and final withdrawal phase alcohol to the point of suppressing alcohol withdrawal and was included after another 4 days of vapor exposure; however lyrica 75mg fast delivery, animals were kept in their home cages and not allowed to re- maintaining blood alcohol levels cheap lyrica 75 mg without prescription. Blood was collected for blood alcohol determi- nations, and observational withdrawal signs were rated during tests 2 and 3 at 0, 8, and 12 hours post withdrawal. Data are Responding for Non-Drug Reinforcers expressed as means SEM. Taken with permission from Roberts AJ, Cole M, Koob GF. Intra-amygdala muscimol decreases operant Several operant schedules have been used to characterize ethanol self-administration in dependent rats. Alcohol Clin Exp the response-disruptive effects of drug withdrawal (37,84). However, response disruption can be caused by any number of variables from motor problems to malaise and decreases in appetite, and thus other measures must be used to rule out nonspecific effects (see the following). Chapter 97: Recent Advances in Animal Models of Drug Addiction 1387 Conditioned Place Aversion 30). Examples of a more specific aspect of withdrawal are animals that have been trained to discriminate pentylenete- The conditioned place preference paradigm can also be used trazol, an anxiogenic-like substance, from saline in alcohol-, to characterize the conditioned aversive effects of drug with- diazepam-, and opiate-dependent animals. Rodents are exposed to one environment while drawal, generalization to the pentylenetetrazol cue has undergoing withdrawal and to another in the absence of a suggested an anxiogenic-like component to the withdrawal withdrawal state. During tests of conditioning, animals are syndrome (14,21). To date, this procedure has been used almost exclusively to study withdrawal from opiate drugs. Ethological Measures Administration of opioid receptor antagonists to animals Animals models of withdrawal that illustrate aversive stimu- rendered physically dependent on morphine via implanta- lus effects can be extended to observational measures, some tion of morphine pellets or repeated injections of an opiate of which may be common to withdrawal from many differ- produces dose-related conditioned place aversions, an effect ent drugs of abuse. Increased anxiety-like responses are ob- that can be observed after only a single conditioning session served following abstinence from cocaine, opiates, benzodi- with the antagonist (27,34). In contrast, the administration azepines, and alcohol (9,25,79,81,85). Measures used to of the same doses of antagonist to opiate-naive animals fails assess anxiety-like responses during include validated animal to produce a conditioned response. Interestingly, the mini- models of anxiety such as the elevated plus-maze, light-dark mum effective dose of an antagonist that produces condi- test, defensive withdrawal, and defensive burying. Although place conditioning typically Reinforcing Effects of Drugs has been used to characterize antagonist-precipitated with- drawal, more recent work indicates its utility for studies of The advantages and disadvantages of models used to evalu- spontaneous withdrawal (10). Clearly, each of the paradigms described has weaknesses, but when combined Brain Stimulation Reward can provide powerful insights into the motivational effects ICSS thresholds have been used to assess changes in systems of drug abstinence. Although no actual negative reinforce- ment is measured using this technique, it is included in ANIMAL MODELS OF ESCALATION IN this section because it constitutes a model of the aversive DRUG INTAKE motivational state associated with the negative reinforce- Animal Models of Sensitization to the ment of drug abstinence in dependent animals. Acute ad- Reinforcing Effects of Drugs ministration of psychostimulant drugs lowers ICSS thresh- old (i. Similar results have been observed with precipitated ioral effects (92). This phenomenon, referred to as withdrawal in opiate-dependent rats (82). Rats showed dra- sensitization, has been implicated in the psychosis that oc- matic increases in ICSS thresholds to naloxone injections curs in some individuals following repeated psychostimu- that occurred in a dose-related manner and at doses below lant use. A role of sensitization in both vulnerability to drug which obvious physical signs of opiate withdrawal were addiction and drug craving has been hypothesized (77). These doses of naloxone had no effect on reward Both self-administration and conditioned place preference thresholds in nondependent animals. Drug Discrimination Intravenous Self-Administration Drug discrimination can be used to characterize both spe- cific and nonspecific aspects of withdrawal. Generalization In self-administration studies, sensitization to the positive to an opiate antagonist provides a more general nonspecific reinforcing effects of drugs is assessed. Typically, animals measure of opiate withdrawal intensity and time course (26, receive daily, noncontingent injections of a drug or placebo. Changes in reward threshold associated with chronic administration of four major drugs of abuse. Reward thresholds were determined using a rate-independent discrete-trials threshold procedure for intracranial self-stimulation (ICSS) of the medial forebrain bundle. A: Rats equipped with intravenous catheters were allowed to self-administer cocaine for 12 straight hours prior to withdrawal and reward threshold determinations. Elevations in threshold were dose- dependent with longer bouts of cocaine self-administration yielding larger and longer-lasting elevations in reward thresholds. Postcocaine anhedonia: an animal model of cocaine withdrawal. B: Elevations in reward thresholds with the same ICSS technique following chronic exposure to alco- hol of approximately 200 mg% in alcohol vapor chambers. Taken with permission from Schulteis G, Markou A, Cole M, et al. Decreased brain reward produced by ethanol withdrawal. C: Elevations in reward thresholds during spontaneous with- drawal after termination of chronic administration of nicotine hydrogen tartrate (9. Taken with permission from Epping-Jordan MP, Watkins SS, Koob GF, Markou A. Dramatic decreases in brain reward function during nicotine withdrawal. D: Elevations in reward thresholds following administration of very low doses of the opiate antagonist naloxone to animals made dependent on morphine using two, 75-mg morphine (base) pellets implanted subcutaneously. Taken with permission from Schulteis G, Markou A, Gold LH, et al. Relative sensitivity to naloxone of multiple indices of opiate with- drawal: A quantitative dose-response analysis. Aster- isks (*) refer to significant differences between treatment and control values. Values are mean SEM Self-administration sessions are then initiated. The rate of Conditioned Place Preference acquisition of self-administration and/or the number of ani- The conditioning procedure used to study sensitization is mals acquiring stable drug self-administration then is deter- identical to that described above except that the dose of mined. Because sensitization is defined as an increase in the conditioning drug or the number of environmental pairings potency and/or efficacy of a drug in producing a particular used typically are those that are ineffective in producing response following its repeated administration, the rate of a conditioned response in previously drug-naive animals. Several laboratories have shown a drug, and place conditioning can be initiated at various that the rate of acquisition of psychostimulant self-adminis- time points following the cessation of drug administration. Alternatively, by employing of sensitization (38,71). The prior administration of am- doses that are subthreshold and threshold for producing a phetamine also increases the acquisition rate of cocaine self- conditioned response, changes in drug potency and efficacy administration (and, conversely, the prior administration of following prior drug exposure can be determined. Using cocaine increases the acquisition rate of amphetamine self- these procedures, long-lasting sensitization and cross-sensi- administration), suggesting that cross-sensitization develops tization to the conditioned reinforcing effects of opiates and to the positive reinforcing effects of psychostimulants. Sensitization to the conditioned reinforcing effects of cocaine. Rats received once daily home cage injections of cocaine or saline for 5 days. Place conditioning (two cocaine; two saline) commenced 3 days later. Cocaine was ineffective in producing a conditioned response after two environmental pairings. In animals with a prior history of cocaine, doses of cocaine as low as5. Ordinate:Conditioning score defined as time in drug-paired environment minus time in saline-paired environment. Asterisks (*) denote significant place conditioning. Taken with permission from Shippenberg TS, Heidbreder C. Sensitization to the conditioned rewarding effects of cocaine: pharmacologic and temporal characteristics. Escalation in Drug Self-Administration reinstated rapidly at a level higher than that seen before Produced by aHistory of Drug Intake abstinence. Similar results have been observed in rats trained to self- A critical issue for the study of the neurobiology of addiction administer heroin intravenously. Two groups of rats were is to develop animal models for the transition between con- trained on 1-hour continuous access to intravenous heroin trolled/moderate drug intake and uncontrolled/excessive self-administration and then one group was allowed access drug intake. Animal models of increased drug intake based for 11 hours continuously. In the animals with 11-hour on prolonged exposure to drug now have been described in access, intake gradually increased over time, whereas in the rats for cocaine, heroin, and alcohol (1–3,76). The animals with 11-hour access to fers depending on the duration of access.

Obtaining a medical history alone has been shown to be Te presence of objective signs of vulvar infammation in the insufcient for accurate diagnosis of vaginitis and can lead to absence of vaginal pathogens after laboratory testing buy discount lyrica 150 mg, along the inappropriate administration of medication discount lyrica 150 mg fast delivery. Terefore cheap lyrica 75 mg fast delivery, with a minimal amount of discharge purchase lyrica 75mg on-line, suggests the possibil- a careful history, examination, and laboratory testing to ity of mechanical, chemical, allergic, or other noninfectious determine the etiology of vaginal complaints are warranted. Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (such as douch- Bacterial Vaginosis ing), and other medications should be elicited. Te three diseases most frequently associated with vaginal discharge BV is a polymicrobial clinical syndrome resulting from are BV (caused by the replacement of the vaginal fora by replacement of the normal hydrogen peroxide producing an overgrowth of anaerobic bacteria including Prevotella sp. Some women experience transient by Candida albicans). Cervicitis also can sometimes cause a vaginal microbial changes, whereas others experience them vaginal discharge. Although vulvovaginal candidiasis (VVC) for a longer intervals of time. Among women presenting for usually is not transmitted sexually, it is included in this section care, BV is the most prevalent cause of vaginal discharge or because it is frequently diagnosed in women who have vaginal malodor; however, in a nationally representative survey, most complaints or who are being evaluated for STDs. Various diagnostic methods are available to identify the BV is associated with having multiple male or female etiology of an abnormal vaginal discharge. Clinical labora- partners, a new sex partner, douching, lack of condom use, tory testing can identify the cause of vaginitis in most women and lack of vaginal lactobacilli; women who have never been and is discussed in detail in the sections of this report dedi- sexually active can also be afected. Nonetheless, women with BV are at increased risk samples of the discharge. Te pH of the vaginal secretions can for the acquisition of some STDs (e. Because surgery, complications of pregnancy, and recurrence of BV. Cover slips are then placed stain (considered the gold standard laboratory method for on the slides, and they are examined under a microscope at diagnosing BV) is used to determine the relative concentration low and high power. If a Gram WBCs without evidence of trichomonads or yeast in this solution Vol. Douching might increase the risk for three of the following symptoms or signs: relapse, and no data support the use of douching for treatment • homogeneous, thin, white discharge that smoothly coats or relief of symptoms. Tinidazole 1 g orally once daily for 5 days Detection of three of these criteria has been correlated with OR results by Gram stain (320). Other tests, including a DNA probe- Clindamycin 300 mg orally twice daily for 7 days based test for high concentrations of G. Although a card test is available (323) or clindamycin (oral or intravaginal) (324). Additional for the detection of elevated pH and trimethylamine, it has low regimens include metronidazole (750-mg extended release sensitivity and specifcity and therefore is not recommended. PCR tablets once daily for 7 days), or a single dose of clindamycin also has been used in research settings for the detection of a variety intravaginal cream, although data on the performance of these of organisms associated with BV, but evaluation of its clinical alternative regimens are limited. Detection of one organism or group of organ- Several studies have evaluated the clinical and microbiologic isms might be predictive of BV by Gram stain (321). However, efcacy of using intravaginal lactobacillus formulations to treat additional evaluations are needed to confrm these associations. Cervical Pap tests have no clinical utility prevention are ongoing. Follow-Up Treatment Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is common, women should be Te established benefts of therapy in nonpregnant women advised to return for evaluation if symptoms recur. Detection are to relieve vaginal symptoms and signs of infection. Other of certain BV-associated organisms have been associated with potential benefts to treatment include reduction in the risk antimicrobial resistance and might determine risk for subse- for acquiring C. Using a diferent treatment regimen might be an option in patients who have a recurrence; however, re- Metronidazole 500 mg orally twice a day for 7 days* treatment with the same topical regimen is another acceptable OR approach for treating recurrent BV during the early stages of Metronidazole gel 0. For women with multiple recurrences after OR completion of a recommended regimen, metronidazole gel Clindamycin cream 2%, one full applicator (5 g) intravaginally at twice weekly for 4-6 months has been shown to reduce recur- bedtime for 7 days† rences, although this beneft might not persist when suppressive * Consuming alcohol should be avoided during treatment and for 24 hours therapy is discontinued (335). Monthly oral metronidazole administered with fuconazole has also been Providers should consider patient preference, possible evaluated as suppressive therapy (337). Women should be advised to refrain from intercourse or to use condoms consistently and correctly during 58 MMWR December 17, 2010 Management of Sex Partners Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i. Seven trials have evaluated afected by treatment of her sex partner(s). Terefore, routine treatment of pregnant women with asymptomatic BV at treatment of sex partners is not recommended. Terefore, evidence is insufcient to assess Allergy or Intolerance to the Recommended the impact of screening for BV in pregnant women at high Therapy risk for preterm delivery (85). Intravaginal clindamycin cream is preferred in case of allergy Similarly, data are inconsistent regarding whether the or intolerance to metronidazole or tinidazole. Intravaginal met- treatment of asymptomatic pregnant women with BV who ronidazole gel can be considered for women who do not toler- are at low risk for preterm delivery reduces adverse outcomes ate systemic metronidazole. Although USPSTF recommends against screen- not be administered to women allergic to metronidazole. Several Treatment is recommended for all pregnant women with additional trials have shown that intravaginal clindamycin symptoms. Additional potential benefts include reducing the risk Providers should be aware that intravaginal clindamycin cream for infectious complications associated with BV during pregnancy might be associated with adverse outcomes if used in the latter and reducing the risk for other infections (other STDs or HIV). Several trials have been undertaken to determine the efcacy of BV treatment among pregnant women. Two tri- HIV Infection als demonstrated that metronidazole was efcacious during BV appears to recur with higher frequency in HIV-positive pregnancy using the 250-mg regimen (338,339); however, women (352). Patients who have BV and also are infected with metronidazole administered at 500 mg twice daily can be used. HIV should receive the same treatment regimen as those who One trial involving a limited number of participants revealed are HIV negative. Some women have symptoms between metronidazole use during pregnancy and teratogenic characterized by a difuse, malodorous, yellow-green vaginal or mutagenic efects in newborns (342,343). However, many women have the antimicrobial agent used to treat pregnant women, oral minimal or no symptoms. Because of the high prevalence therapy is preferred because of the possibility of subclinical of trichomoniasis in clinical and nonclinical settings upper-genital–tract infection. Screening for Recommended Regimens for Pregnant Women T. OR Diagnosis of vaginal trichomoniasis is usually performed Clindamycin 300 mg orally twice a day for 7 days by microscopy of vaginal secretions, but this method has a Vol. FDA-cleared tests for trichomoniasis in women include Recommended Regimens OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic Metronidazole 2 g orally in a single dose capillary fow dipstick technology, and the Afrm VP III OR (Becton Dickenson, San Jose, California), a nucleic acid probe Tinidazole 2 g orally in a single dose test that evaluates for T. Each of these tests, which are performed on vaginal secretions, Alternative Regimen have a sensitivity of >83% and a specifcity of >97%. Both Metronidazole 500 mg orally twice a day for 7 days* tests are considered point-of-care diagnostics. Te results of * Patients should be advised to avoid consuming alcohol during treatment the OSOM Trichomonas Rapid Test are available in approxi- with metronidazole or tinidazole. Abstinence from alcohol use should mately 10 minutes, whereas results of the Afrm VP III are continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole. Although these tests tend to be more sensitive than those requiring vaginal wet preparation, false positives might occur, especially in populations with a Te nitroimidazoles comprise the only class of drugs use- low prevalence of disease. Of Culture is another sensitive and highly specifc commer- these drugs, metronidazole and tinidazole are available in the cially available method of diagnosis. Among women in whom United States and are cleared by the FDA for the treatment of trichomoniasis is suspected but not confrmed by microscopy, trichomoniasis. In randomized clinical trials, the recommended vaginal secretions should be cultured for T. While the metronidazole regimens have resulted in cure rates of approxi- sensitivity of a Pap test for T. Randomized controlled trials compar- PCR assay for detection of gonorrhea and chlamydial infec- ing single 2-g doses of metronidazole and tinidazole suggest tion (Amplicor, manufactured by Roche Diagnostic Corp. Several other topically applied antimicrobials ASR found sensitivity ranging from 74%–98% and specifcity occasionally have been used for treatment of trichomoniasis; of 87%–98% (357–359). Laboratories that use the Gen-Probe however, these preparations likely are no more efective than APTIMA Combo2 test for detection of N. Because of the high rate of reinfection among patients in In men, wet preparation is not a sensitive test, and no whom trichomoniasis was diagnosed (17% were reinfected approved point-of-care tests are available. Culture testing within 3 months in one study), rescreening for T. While to infect oral sites, and rectal prevalence appears low in MSM most recurrent T. Low-level metronidazole resistance has natal morbidity. Although some trials suggest the possibility of been identifed in 2%–5% of cases of vaginal trichomoniasis increased prematurity or low birth weight after metronidazole (362,363), but high-level resistance only rarely occurs. Treatment respond to tinidazole or higher doses of metronidazole. In addition, many infection of the newborn and further sexual transmission. All symptomatic pregnant women should with metronidazole 500 mg orally twice daily for 7 days.

The results of these methadone dose ministrative citations to criminal prosecution discount 150 mg lyrica with amex. Clinics are clinical response have not been observed consistently generic 75 mg lyrica overnight delivery. One often located in old buildings that have been converted to study found significant correlations between oral dose and comply with regulations but that were never intended for methadone concentration best 75 mg lyrica, but only among patients who medical use purchase 150 mg lyrica visa. At the present time, it is estimated that approxi- complained of low dosing (26). These findings suggest that mately 179,000 patients are being maintained on metha- some patients may be more sensitive to dosage changes and done or LAAM at 940 or more sites, and this number repre- that clinical response, including subjective complaints, is a sents only about 20% of the opioid addicts in the United more important guide to adequate dose levels than specific States (21). No controlled studies have been done examin- This treatment-program regulatory system has been ing doses higher than 120 mg; thus, the upper limits of under increasing criticism since the early 1990s. Criticism dosing effectiveness are not well understood. The importance approved for detoxification or maintenance that are in of these criticisms has been underlined by the recent increase Schedules III, IV, and V (27). Physicians who choose to in heroin addiction (22), by evidence that methadone main- treat persons with opioid dependence under the new regula- tenance reduces the incidence of hepatitis and HIV infec- tions will need to notify the Secretary of Health and Human tion, and by the lack of coverage for agonist maintenance Services in writing of their intent and to show that they 1510 Neuropsychopharmacology: The Fifth Generation of Progress are qualified to provide addiction treatment by virtue of prenorphine for its own positive subjective effects (33,34). No physician would be allowed Only one study published to date has characterized the be- to treat more than 30 patients at one time without special havioral and physiologic effects of a wide range of buprenor- approval, according to the legislation as it is now proposed. The re- This change in the regulations will be especially impor- sults indicated that buprenorphine, given intravenously, has tant for buprenorphine and the buprenorphine-naloxone a low abuse liability in this population. The to be treated in the current methadone or LAAM system. Parenteral misuse of of medical care, to make it more readily available, and to the combination by persons addicted to opioids would be improve its quality. Buprenorphine is marketed internationally as an combination product in an office-based setting represents analgesic (both without naloxone and with naloxone to an innovative alternative to the restrictive methadone or deter abuse) and as a treatment for opioid addiction. The most widespread use of buprenorphine is in France, where use of this new drug combination should expand the avail- it was approved for the latter indication in 1996. In the ability of agonist maintenance treatment with a relatively United States, buprenorphine is currently approved only low risk for abuse or diversion. In addition, the partial ago- as an analgesic for parenteral administration; approval for nist activity of buprenorphine results in a much lower risk of opioid addiction treatment is pending. Buprenorphine has overdose death than is the case with methadone or LAAM. Most of the Antagonist Maintenance early clinical trials used a sublingual solution of buprenor- phine formulated in a hydroethanolic vehicle, although a Naltrexone is the prototypical opioid antagonist used in more commercially suitable sublingual tablet formulation abstinence maintenance therapy; this drug blocks the effects is now used. Naltrexone has no opioid agonist effects and is full agonists such as methadone and LAAM is the plateau a competitive opioid antagonist. It is orally effective and effect of -agonist activity. Parenteral doses as high as 12 can block opioid effects for 24 hours when administered as mg intravenously (28) have been given to opioid-intolerant a single daily dose of 50 to 60 mg. Higher doses usually patients with only limited adverse effects (e. Numerous large trials have con- they will provide more cross tolerance to heroin and other firmed the utility of buprenorphine for agonist maintenance opioids during the 24-hour dosing period (38). These studies have included comparisons of bu- favorable adverse event profile (nausea is typically the most prenorphine with placebo (29,30), a buprenorphine-nalox- common side effect), naltrexone is generally not favored by one combination with placebo (30), and a multiple-dose opioid addicts because, unlike opioid agonists and partial comparison study (31). In one of the most recent trials (32), agonists, it produces no positive, reinforcing effects. Fur- buprenorphine (given three times weekly) was compared thermore, it may be associated with the precipitation of an with LAAM (given three times weekly) and methadone opioid withdrawal syndrome if it is used too soon after (given daily) in a 17-week study. Mean retention in treat- opioid use stops, an effect that can be minimized by admin- ment was higher for buprenorphine, LAAM, and high-dose istering a naloxone challenge test before giving naltrexone. Opioid- more than 25 years, work continues on increasing medica- positive urine samples decreased most for the LAAM-treated tion compliance and improving outcomes. Some of these group and least for low-dose methadone. Patient self-reports more recent efforts include work to develop a depot form of opioid use did not differ among the groups, but they that will block opioid effects for 14 to 28 days. This dosage showed decreases of about 90% over the course of the study. At present, a Buprenorphine has the potential to be abused and can patient treated with naltrexone has only to stop the medica- produce addiction. However, most persons who abuse bu- tion for 1 to 3 days to experience the full effects of subse- prenorphine initiated opioid use with other drugs. A depot dosage form of naltrexone would may take the form of using greater than prescribed dosages provide more time for patients to overcome ambivalence for analgesia, using buprenorphine in place of a more de- about stopping opioid use and could result in more long- sired but less available opioid such as heroin, or using bu- term success than has currently been the case. Another var- Chapter 105: Treatment of Opioid Addiction 1511 iant on antagonist treatment is nalmefene, an orally effective weeks or months of treatment with reductions in frequency but somewhat longer-acting (about 48 hours at dosages of to biweekly or monthly depending on progress. Results showed a dence and abuse are ambivalent about stopping drug use dose–response relationship with the minimal condition (41,42). This ambivalence presents a therapeutic challenge doing significantly worse than standard and enhanced coun- because it contributes to varying levels of motivation to seling doing the best overall; however, about 30% of pa- enter and remain in treatment, to early dropout, and to tients did well in the minimal counseling condition. This partial or (in some cases) nontreatment response. Studies study clearly demonstrated the positive benefits achieved by have emphasized that treatment providers must be aware of drug counseling and showed that, for most patients, coun- this 'normal' ambivalence and make reasonable efforts to seling is necessary to bring out the maximum benefits of resolve it in favor of treatment participation and cessation agonist maintenance. Suggestions have been made regarding Most counseling is individual, one on one, but some initial steps to maximize the chances for engagement in programs use group therapy exclusively. These include avoiding programs use groups only for selected patients with focal unnecessary delays in entering treatment, expressing a hope- problems such as HIV disease, posttraumatic stress disorder, ful and nonjudgmental attitude, performing a comprehen- homelessness, loss of close personal relationships, or not at sive evaluation, and developing a treatment plan that is re- all. Some programs have self-help groups or with medical, psychiatric, legal, employment, and family that meet regularly on site. Counselors, like psychothera- or social issues that preexist or result from the addiction. This Research has found that addressing these additional prob- variability seems more related to the ability to form a posi- lems can be helpful, but they are complex and require coor- tive, helping relationship with the patient than to specific dination between agonist pharmacotherapy staff and other techniques (46). Contingency management techniques are always in- The most common type of psychosocial service in opioid cluded in drug counseling, if for nothing else than to fulfill agonist treatment is individual drug counseling. Counselors regulations about requiring progress in treatment as a condi- are typically persons at the masters level or below who de- tion of providing take-home doses, and studies have shown liver a behaviorally focused treatment aimed to identify spe- that they can be very helpful. For example, an opportunity cific problems, to help the patient access services that may to receive take-home medications in return for drug-free not be provided in the clinic (e. Functions that counselors perform in- a clear use in general clinical practice because it is easily clude monitoring methadone and LAAM doses and request- applied and costs little or nothing beyond standard program ing changes when needed, reviewing urine test results, re- costs. More flexibility in dispensing take-home doses as con- sponding to requests for take-homes doses, assisting with tingencies for positive behaviors could be a positive effect family problems, assessing and responding to crises, writing of the regulatory reforms described earlier. Although nicotine (tobacco) use is not always included, especially useful for patients with alcohol abuse or depen- the increased emphasis on adverse health effects of smoking dence. Maintenance, counseling, and contingency manage- has resulted in more attention to stop smoking at all levels, ment are often combined in complex ways, as seen in the including drug counseling. Counselors and patients typi- following vignette: cally have weekly, 30- to 60-minute sessions during the first A 42-year-old man presented for his sixth episode of 1512 Neuropsychopharmacology: The Fifth Generation of Progress methadone maintenance. One study done in Philadelphia (49) found that ism and was using cocaine regularly. He had done fairly among 110 patients who were administratively discharged well on methadone as far as illicit opioid use was concerned, or dropped out of a Veterans Affairs (VA) maintenance but his clinic attendance and ability to comply with clinic program, 8. Among the 43 patients (from among the 110) in treatment for about a year, then become angry over his who were discharged for failing to adhere to a treatment inability to obtain take-home doses because of positive contract, five (11. None of these breathalyzer tests, drop out, and have a relapse to opioid five patients were in treatment at the time of death, and all use. He had frequently been offered inpatient detoxification died as a result of overdoses. When he for violating program rules (mainly drug dealing or giving presented for treatment most recently, he was unemployed a false urine specimen). These results are consistent with (secondary to alcohol problems) and living with his parents, data from New South Wales, Australia, where there has who were threatening to put him out because of drug use. Although it is He agreed that, as part of his treatment plan, he would go estimated that 20% to 30% of the heroin addicts in New into the hospital for alcohol detoxification and stabilization South Wales are receiving methadone maintenance, only on methadone and then be discharged to maintenance ther- 3% of the 953 heroin-related fatalities occurred among pa- apy. After inpatient discharge, he attended AA-style coun- tients receiving methadone maintenance (50). These data seling, requested daily alcohol breath tests, and turned down emphasize the fine line between contingencies maintained an offer to return to his job at the liquor store. He remained in programs and the dangers associated with program dis- stable for 3 years on 65 mg per day of methadone with no missal. Rather, a series hesitant to suspend patients from maintenance treatment of coordinated steps was necessary to achieve a positive treat- for positive urine test results alone. Although not demonstrated in this vignette, especially relevant in environments where the potency of family therapy is another intervention that can be combined heroin is high, such as Philadelphia, where the average 'bag' with agonist therapy and other psychosocial interventions, of heroin is now 71% pure (22). Therapeutic communities are another psychosocial ap- Although counseling and other services are effective en- proach that is often useful for opioid addicts who have a hancements of agonist treatment, adherence is often an long history of addiction and a strong motivation to become issue, and clinics vary in the way they respond to this prob- drug free. These programs are very selective, self-governing, lem.