PsychopharmacologyN E W S L E T T E R

Volume 7, Issue 3 September 2004

THIS NEWSLETTER IS SUPPORTED BY UNRESTRICTED EDUCATIONAL GRANTS FROM:

THE BAY AREA PSYCHOPHARMACOLOGY NEWSLETTER

Douglas Del Paggio, PharmD, MPA, Editor2000 Embarcadero Cove, Suite 400Oakland, California 94606-5300

BAY AREA PSYCHOPHARMACOLOGYNEWSLETTER

Editor:Douglas Del Paggio, PharmD, MPA2000 Embarcadero Cove, Suite 400Oakland, California 94606-5300(510) 567-8110 FAX (510) 567-6850email: delpaggio@bhcs.mail.co.alameda.ca.us

Contributors:Alameda County:Richard P. Singer, MDDouglas Del Paggio, PharmD, MPAAlice Myong, PharmD

San Francisco County:Jimmy Jones, MDMary Ann Sullivan, PharmDRenée Spencer, MA, PhDTalia Puzantian, Pharm D

San Mateo County:Celia Moreno, MDBarbara Liang, PharmD

Graphic Designer: Janie Chambers

INSIDE THIS ISSUE

Buprenorphine & Office Based Opioid Therapy (OBOT) . . .2County Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3CME Calendar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Continued on page 2

CONTINUING

MEDICAL EDUCATION

The Bay Area Psychopharmacology Newsletteris now available on the Alameda CountyBehavioral Health Care Services website:http://bhcs.co.alameda.ca.us/ at the top ofthe page in the list of Quick Links.

Nora Tu, UCSF PharmD Candidate and Renee Spencer, MA, PhD

INTRODUCTIONOlanzapine (Zyprexa) is an atypical antipsychotic indicated for

the treatment of schizophrenia and acute mixed or manic episodesassociated with bipolar I disorder. Recently (March 2004), olan-zapine intramuscular (IM) was approved by the FDA for the treat-ment of agitation associated with schizophrenia and bipolar Imania. Agitation associated with neuropsychiatric disorders suchas schizophrenia and bipolar disorder is common and often re-quires treatment. Parenteral administration of antipsychotics isoften favored for controlling acute agitation due to its rapid on-set of action. It is also beneficial when agitated patients refuseto comply with oral medications. In the past, typical an-tipsychotics such as haloperidol and benzodiazepines such aslorazepam were the only available treatment options for acuteagitation. However, typical antipsychotics are often associ-ated with undesirable side effects, including hypotension andextrapyramidal symptoms (EPS). Lorazepam is also associ-ated with certain risks such as lethargy and increased cogni-tive impairment. Ziprasidone (Geodon) IM, approved by theFDA in June 2002, was the first atypical antipsychotic availablein a short-acting intramuscular formulation. Ziprasidone IMhas shown comparable efficacy to haloperidol IM, and was also better tolerated, especially in motor side effects such as EPS.The newly formulated olanzapine IM may be another safe and effective alternative for managing agitation, possibly with amore rapid onset of action and reduced motor and sedating side effects.

CLINICAL PHARMACOLOGY & PHARMACOKINETICSOlanzapine’s antipsychotic activity is believed to be mediated through the combined inhibition of dopamine and serotonin type

2 (5HT2) receptors.1

Olanzapine IM is rapidly absorbed, with peak plasma concentrations occurring within 15-45 minutes. 1The maximum plasma

concentration of olanzapine IM is approximately 5 times higher than that of oral olanzapine at an equal dose. Area under thecurve (AUC) and half-life (t1/2) are similar for IM and oral doses. The half-life of olanzapine ranges from 21 to 54 hours, andthe apparent plasma clearance ranges from 12 to 47 L/hr.

SAFETY AND EFFICACYThe safety and efficacy of olanzapine IM in the treatment of agitation was established in 3 short-term (24 hours of IM treatment)

double blind, placebo-controlled studies in agitated inpatients. Two studies compared olanzapine IM and haloperidol IM inschizophrenic patients (total n=581), and one study compared olanzapine IM and lorazepam in patients with bipolar I disorder(n=201). In all 3 studies, the Positive and Negative Syndrome Scale Excited Component (PANSS-EC), used to determine changesin levels of agitation, was the main measure of outcome. Other measures used included: Agitation-Calmness Evaluation Scale

Intramuscular Olanzapine:Treatment for Acute Agitation

(ACES), Agitated Behavior Scale, and the Cohen-MansfieldAgitation Inventory (for patients with dementia).

In the studies 2,3 comparing olanzapine IM (1-3 injections, ad-ministered at 2.5, 5.0, 7.5, 10.0 mg) with haloperidol IM (7.5mg) and placebo, olanzapine IM exhibited a dose-response

Biological Correlates of PTSDByron Wittlin, MDSeptember 3rd 2004 12-1pm SFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Long-term Management ofSchizophreniaJohn Csernansky, MDSept 24th 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Treatment-Resistant PTSDMark Hamner, MDOct 1st 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Social Anxiety: Diagnosis &TreatmentOwen Wolkowitz, MDOct 29th 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Legal Issues in PsychopharmacologyDavid Naimark, MD, FAPANov 12th 2004 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Treatment of Agitation in DementiaPierre Tariot, MDDec 3rd 2004 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Page 2 Bay Area Psychopharmacology Newsletter September 2004 September 2004 Bay Area Psychopharmacology Newsletter Page 5

relationship. Both olanzapine IM (at all four doses) andhaloperidol IM resulted in a significantly greater reductionin agitation than placebo. In addition, olanzapine (at the10 mg dose) appears to have a more rapid onset of actionthan haloperidol, as shown by its slightly greater reductionof agitation at 15, 30, and 45 minutes following the firstinjection. Furthermore, olanzapine IM appears to have abetter safety profile than haloperidol IM. Patients treatedwith olanzapine IM experienced a significantly lower inci-dence of acute dystonia (0%) and parkinsonism (0%) com-pared with those treated with haloperidol IM (7% and16.7%, respectively). Finally, olanzapine did not result insignificant changes in hypotension, ECG, or QTc interval.Somnolence was one of the most commonly reported ad-verse events.

In the study 4 comparing olanzapine IM (1-3 injectionsof 10 mg each) with lorazepam (2mg, first 2 injections;1mg, third injection) and placebo, patients treated witholanzapine showed a significantly greater reduction inagitation than patients treated with either placebo or lo-razepam (p<0.001) at 30, 60, 90, and 120 minutes afterthe first injection. There were no significant differences insafety measures (e.g., incidence of EPS, acute dystonia;QTc interval changes) among the three treatment groups.Again, somnolence was the most frequent treatment-emer-gent adverse event reported, occurring at 13.1% in theolanzapine treatment group, 9.8% in the lorazepam group,and 5.9% in the placebo group. Other adverse events as-sociated with olanzapine treatment included nausea anddizziness. There has been a European report 7 of posturalhypotension with the administration of the 10mg dose(12%) vs. haloperidol 7.5mg (3%). Patients should be as-sessed prior to administration of subsequent IM injections.

DOSING AND ADMINISTRATIONThe efficacy of olanzapine IM in controlling agitation in

schizophrenia and bipolar disorder was demonstrated inthe dose range of 2.5mg to 10mg.1 The recommended doseis 10mg, although a lower dose of 5mg to 7.5mg may alsobe used depending on clinical factors. In geriatric patients,a dose of 5mg per injection is recommended. In clinical tri-als, about 75% of the olanzapine treated patients neededonly one intramuscular dose.2,4 If persisting agitation re-quires additional IM doses, subsequent doses up to 10mgmay be given with a maximum daily dose of 30mg (three10mg doses administered 2-4 hours apart). However, effi-cacy of repeated doses has not been studied.

COSTOlanzapine IM comes as a 10mg/2ml single-dose vial,

which needs to be used within 1 hour of reconstitution.The cost is $21 per vial, which is less than that of ziprasi-done IM (20mg/vial @ $48), and more than that of ei-ther lorazepam and/or haloperidol IM (Table 1). We areawaiting comparison studies between these atypical an-tipsychotic IM agents in regards to cost effectiveness andefficacy, as well as advantages over the current standardof care.

SUMMARYRecently developed intramuscular formulations of atypical

antipsychotics (ziprasidone and olanzapine) offer rapid and ef-fective reduction in acute agitation, with improved patient tol-erability and easy transition to oral therapy.

In particular, studies show that olanzapine IM is as effectiveas conventional treatment options (haloperidol, lorazepam) inreducing acute agitation in patients with schizophrenia orbipolar disorder. It may also have a somewhat faster onset ofaction. In addition, olanzapine IM has a more favorable ad-verse effect profile, especially in motor side effects such as EPS.Olanzapine IM is approved for acute use only; if long-termtherapy is needed, patients may be safety transitioned to treat-ment with oral olanzapine tablets. At this time, no head-to-head studies have been conducted with ziprasidone IM.

Table 1.Cost Comparison for Intramuscular

Olanzapine, Haloperidol, and LorazepamSingle Dose

Drug Quantity Cost/Vial Cost/DayOlanzapine IM 10 mg/vial $21 $11-$63Ziprasidone IM 20 mg/vial $48 $24-$96Haloperidol IM 5 mg/vial $2 $1-$8Lorazepam IM 2 mg/vial $3 $3-12

* cost/dose and cost/day are based on Avg.Wholesale Price ofdrug;cost/day is based on minimum and maximum recommendeddaily dose.

Additional studies are necessary to determine the overall clini-cal and economic implications of olanzapine IM in comparisonwith alternative treatment options.

References available upon request.

Ryan Cello, UCSF PharmD Candidate and Julie DeBoard,PharmD Candidate, Renée Spencer, PhD

According to the Office of National Drug Control Policy,an estimated 898,000 people in the United States chroni-cally used illicit opioids in 2002. Opiate addiction affectspeople in all walks of life and estimated costs are up to 20billion dollars per year. This takes into account cost of treat-ment, lost productivity of employees, crime, healthcare andmany other factors. A recent study showed that only100,000 patients are currently receiving treatment for theirdisease. This is due in part to the limited access to treatmentcenters experienced by these patients.

This limited access to treatment centers helped lead to thepassing of the Drug Addiction Treatment Act of 2000(DATA 2000). The DATA 2000 expands the clinical con-text of medication-assisted opioid addiction treatment by

expanding qualified physicians’ ability to prescribe and dis-pense specific schedule III, IV & V narcotic medicationsin settings other than the traditional opioid treatment pro-gram such as a methadone clinic. This new model for thetreatment of opioid addiction is referred to as “officebased opioid therapy”(OBOT).

Until the passing of the DATA 2000, the main thera-peutic options available for opioid addiction therapywere methadone, levo-alpha-acetyl-methadol (LAAM),and naltrexone. These drugs are used for detoxificationto help alleviate the symptoms of withdrawal while thepatients adjust to a drug free state. They can be contin-ued as part of a long-term treatment program, can be sub-stituted with behavioral therapy or used concomitantlywith behavioral therapy.

Methadone has been used as an effective opiate detoxi-fication treatment for the past 30 years. It has a half life of15-22 hours and the ability to block opiate withdrawal fora duration of 24 hours. Similar to methadone, LAAM hasthe ability to block withdrawal symptoms and has beenfound to be an effective treatment for opiate addiction. Ithas a duration of action of 72 hours and thus only needsto be dosed orally three times a week. Naltrexone is an opi-ate antagonist that can block the effects of opiates by pref-erentially binding to the opiate receptors and displacingany opiates that are bound. Naltrexone has long lasting ef-fects that can last from 1-3 days depending on the dose.Naltrexone is mainly used as an antidote for patients suf-fering from opiate overdose but it can also be used by for-mer addicts to prevent relapse.

The main problem with methadone and LAAM is thatfederal regulations allow only an Opioid AgonistTreatment Program possessing a current, valid certifica-tion from SAMHSA to dispense opioid schedule II drugsin the treatment of opioid addiction. This means that forpatients to get their medications they need to go to a des-ignated opioid treatment program such as a methadoneclinic. Many potential patients have limited access to ad-diction treatment due to the small number of clinics, in-ability of a primary care physician to prescribe addictiontreatment medications and the stigma associated withmethadone clinics.

With the passing of the DATA 2000 physicians nowhave the ability to prescribe schedule II-V drugs for thetreatment of opiate addiction. Both Subutex andSuboxone, schedule III drugs, are now available for usein the treatment of opioid dependence. Suboxone comesas a sublingual tablet that contains buprenorphine HCland naloxone HCl dihydrate at a ratio of 4:1 buprenor-phine:naloxone (ratio of free bases). Subutex is a sublin-gual tablet containing only buprenorphine HCl.

The mu-opioid receptor is involved in causing eupho-ria and analgesia. Naloxone is an antagonist at the mu-opioid receptor. Buprenorphine is a partial agonist at themu-opioid receptor. At low doses it behaves as an opiateagonist but when it is given in high doses it behaves as-both an opiate agonist and an antagonist. Buprenorphine

Buprenorphine & Office BasedOpioid Therapy (OBOT)

Intramuscular Olanzapine ... continued

has a high affinity for the opiate receptor and if it is givenwith heroin or methadone it will displace either from thereceptor.

Suboxone and Subutex come as a 2mg tablet and a 8mgtablet. An 8mg Suboxone sublingual tablet has a half-life =37hours. The naloxone is included in the Suboxone formu-lation to discourage patients from injecting the medica-tion due to the fact that when injected the naloxone isfully absorbed and can lead to acute opiate withdrawal.

In a Cochrane systemic review that evaluated the effectsof buprenorphine maintenance against placebo andmethadone maintenance, it was found that buprenor-phine is an effective intervention for use in the mainte-nance treatment of heroin dependence. This reviewincluded 13 randomized clinical trials with 12 of thembeing double-blind. Although buprenorphine is not su-perior to methadone, in regards to patient retention andsuppression of heroin use, buprenorphine was found tobe statistically superior to placebo at all doses.

The passing of the DATA 2000 allows buprenorphine,a schedule III drug, to be prescribed in a setting otherthan the traditional methadone clinic. Only a qualifiedphysician, which is defined in the DATA 2000 as a physi-cian who is licensed under State law, has DEA registra-tion to dispense controlled substances, has the capacity torefer patients for counseling and ancillary services, willtreat no more than 30 such patients at any one time, andis qualified by certification, training, and/or experienceto treat opioid addiction, can prescribe buprenorphine.Ultimately, the DATA 2000 may improve access to treat-ment for many patients seeking detoxification. References available upon request.

Bay A

rea

Alameda CountyB E H AV I O R A L H E A LT H C A R E

September 2004 Bay Area Psychopharmacology Newsletter Page 3

Third in Alameda County BHCS’ landmarkseries of atypical antipsychotic pharmacoeco-nomic studies, quetiapine (Seroquel) was re-

viewed in a prospective, mirror-design, naturalisticanalysis spanning two years for each patient. All utilizedmental health services and correlating costs for patientsstarted on quetiapine therapy between 8/28/1997 and4/2/2003 were captured. Clinical function was assessedat baseline and again at 6 months using the Positive andNegative Syndrome Scale (PANSS).

Fifty patients who stayed on quetiapine for a period of 12months were included in this study. Patients were pri-marily female (56 %) and had a mean age of 44 years.Most (96%) had a diagnosis of psychosis, schizophrenia,schizo-affective or other major thought disorder.

Reviewing service utilization and costs data pre andpost quetiapine initiation (charts #1 and #2 respectively),inpatient hospitalization days dropped by 72%($213,000), crisis visits were reduced by 60%, outpatientservices increased and medication costs rose to 4 times thecost of previous therapy.

In regards to efficacy, many patients demonstrated asignificant improvement in their symptoms, capturedthrough a reduction in their PANSS total score. 37% ofthe patients achieved a score reduction of 20% or more(clinically significant improvement), and four of thesepatients had score reductions of over 60%.

Pharmacoeconomic Outcome Study: Quetiapine

In summarizing the overall cost impact of quetiapine, initiation of themedication increased the overall mean costs by $144 per patient/month(chart #3). But, when including all services utilized (including inpatienthospitalization, PES, outpatient services & medication) a mean savingsof $12 per patient/month was realized.

This result is comparable with the previous two completed atypicalantipsychotic studies of olanzapine and risperidone, which had a meanoverall cost savings of $296 and $262 respectively. We are actively col-lecting data on both ziprasidone (Geodon) and aripiprazole (Abilify)to further our understanding of these newer agents.

Chart 3

Chart 2

Chart 1

Page 4 Bay Area Psychopharmacology Newsletter September 2004

Alameda County

INTRODUCTION:Due to recent FDA approval and few published trials of this med-

ication, there is much we need yet to learn regarding the indication,medication dose and usage in the outpatient population. Like allother antipsychotics, long-acting risperidone is not a panacea for thetreatment of psychosis or non-compliance. In addition, its extremecost ($600-$1,100 per month) is an additional factor to evaluate.

Presently, due to the paucity of data, we have to base our decisionson what is currently reported in the few published studies. As moreinformation becomes available, these guidelines will be updated.

GUIDELINES

Stabilized patients receiving effective antipsychotic treatmentshould not be abruptly switched to IM long-acting risperidonebased solely upon potential TD risk, non-compliance, or efficacyfactors alone. Until more information is available, a combinationof sub-optimal treatment, non-compliance risk and a response tooral risperidone is required. In addition, it is necessary to assess thepatient’s willingness to switch treatment and risk psychiatric re-lapse.

Prior to the initiation of the IM long-acting formulation, a 2-4week oral trial of risperidone is necessary to assess efficacy/response,evaluate adverse effects and rule out any untoward reactions.Patients switching from other IM long-acting medication must alsoreceive this oral trial.

■ The starting dose is 25mg IM Q 2weeks. ■ Due to its long half-life, peak levels from one dose occur at

~ 5 weeks after the first injection, and efficacy may be delayed for that same period. Therefore, concomitant oralrisperidone is necessary for the initial 3 weeks of therapy.

■ With continuous every 2 week dosing, steady state occurs atapproximately 8 weeks. Patients should be kept on 25mg IMx 8 weeks (2 months or 4 injections) before any dose adjust-ment is made.

EVIDENCE-BASED DATA:1. In regards to improving compliance:

■ In Patel1 6 month outpatient study (n=81): 43% were not fully adherent with injections, and 37% discontinued treat-ment within that same period

■ In Kane2 12 week trial (n=400): over 50% of patients receiving IM long-acting risperidone dropped-out

■ In Fleischhacker3 12 month, open-label, non-US trial: 35%of patients did not complete the study.

2. In regards to adverse effects:■ In Fleischhacker’s study (n=615)

❖ 6 deaths (4 suicides)❖ 4 reported cases of emergent tardive dykinesia (TD)

■ Reported EPS rates with IM risperidone long-acting:

■ Concomitant antiparkinsonian meds:

EPS Rates Kane FleischhackerPlacebo 13% -25mg IM q 2 weeks 10% 21%50mg IM q 2 weeks 24% 27%

Antiparkinsonian Kane FleischhackerPlacebo 13% -25mg IM q 2 weeks 12% 23%50mg IM q 2 weeks 23% 34%

Efficacy Kane FleischhackerPlacebo 17% -25mg IM q 2 weeks 47% 55%50mg IM q 2 weeks 48% 56%

■ Concomitant benzodiazepines were used in 45% (25mg IM q 2 weeks) and 54% (50mg IM q 2 weeks) of the patientsin the Fleischhacker study.

3. In regards to efficacy (defined as > 20% reduction in PANSSscore):

4. In regards to initiation and switching:■ In clinical trials and studies (two published and one unpub-

lished), all patients received oral administration of risperidoneprior to administration of IM long-acting risperidone:❖ Kane: one-week open-label oral run-in titrated to 4mg per

day❖ Fleischhacker: two-week oral run-in to 1-6mg per day❖ Chue4: eight-week oral run-in to 2-6mg per day

■ In Turner5 12-week open-label, non-US trial: previouslystabilized depot patients were switched directly to IMlong-acting risperidone.❖ 51% required concomitant antipsychotics or sedative/

hypnotics❖ 27% received supplemental oral risperidone

Alameda Co. BHCS Long-acting IM Risperidone (Consta) Guidelines

References available upon request.

Page 2 Bay Area Psychopharmacology Newsletter September 2004 September 2004 Bay Area Psychopharmacology Newsletter Page 5

relationship. Both olanzapine IM (at all four doses) andhaloperidol IM resulted in a significantly greater reductionin agitation than placebo. In addition, olanzapine (at the10 mg dose) appears to have a more rapid onset of actionthan haloperidol, as shown by its slightly greater reductionof agitation at 15, 30, and 45 minutes following the firstinjection. Furthermore, olanzapine IM appears to have abetter safety profile than haloperidol IM. Patients treatedwith olanzapine IM experienced a significantly lower inci-dence of acute dystonia (0%) and parkinsonism (0%) com-pared with those treated with haloperidol IM (7% and16.7%, respectively). Finally, olanzapine did not result insignificant changes in hypotension, ECG, or QTc interval.Somnolence was one of the most commonly reported ad-verse events.

In the study 4 comparing olanzapine IM (1-3 injectionsof 10 mg each) with lorazepam (2mg, first 2 injections;1mg, third injection) and placebo, patients treated witholanzapine showed a significantly greater reduction inagitation than patients treated with either placebo or lo-razepam (p<0.001) at 30, 60, 90, and 120 minutes afterthe first injection. There were no significant differences insafety measures (e.g., incidence of EPS, acute dystonia;QTc interval changes) among the three treatment groups.Again, somnolence was the most frequent treatment-emer-gent adverse event reported, occurring at 13.1% in theolanzapine treatment group, 9.8% in the lorazepam group,and 5.9% in the placebo group. Other adverse events as-sociated with olanzapine treatment included nausea anddizziness. There has been a European report 7 of posturalhypotension with the administration of the 10mg dose(12%) vs. haloperidol 7.5mg (3%). Patients should be as-sessed prior to administration of subsequent IM injections.

DOSING AND ADMINISTRATIONThe efficacy of olanzapine IM in controlling agitation in

schizophrenia and bipolar disorder was demonstrated inthe dose range of 2.5mg to 10mg.1 The recommended doseis 10mg, although a lower dose of 5mg to 7.5mg may alsobe used depending on clinical factors. In geriatric patients,a dose of 5mg per injection is recommended. In clinical tri-als, about 75% of the olanzapine treated patients neededonly one intramuscular dose.2,4 If persisting agitation re-quires additional IM doses, subsequent doses up to 10mgmay be given with a maximum daily dose of 30mg (three10mg doses administered 2-4 hours apart). However, effi-cacy of repeated doses has not been studied.

COSTOlanzapine IM comes as a 10mg/2ml single-dose vial,

which needs to be used within 1 hour of reconstitution.The cost is $21 per vial, which is less than that of ziprasi-done IM (20mg/vial @ $48), and more than that of ei-ther lorazepam and/or haloperidol IM (Table 1). We areawaiting comparison studies between these atypical an-tipsychotic IM agents in regards to cost effectiveness andefficacy, as well as advantages over the current standardof care.

SUMMARYRecently developed intramuscular formulations of atypical

antipsychotics (ziprasidone and olanzapine) offer rapid and ef-fective reduction in acute agitation, with improved patient tol-erability and easy transition to oral therapy.

In particular, studies show that olanzapine IM is as effectiveas conventional treatment options (haloperidol, lorazepam) inreducing acute agitation in patients with schizophrenia orbipolar disorder. It may also have a somewhat faster onset ofaction. In addition, olanzapine IM has a more favorable ad-verse effect profile, especially in motor side effects such as EPS.Olanzapine IM is approved for acute use only; if long-termtherapy is needed, patients may be safety transitioned to treat-ment with oral olanzapine tablets. At this time, no head-to-head studies have been conducted with ziprasidone IM.

Table 1.Cost Comparison for Intramuscular

Olanzapine, Haloperidol, and LorazepamSingle Dose

Drug Quantity Cost/Vial Cost/DayOlanzapine IM 10 mg/vial $21 $11-$63Ziprasidone IM 20 mg/vial $48 $24-$96Haloperidol IM 5 mg/vial $2 $1-$8Lorazepam IM 2 mg/vial $3 $3-12

* cost/dose and cost/day are based on Avg.Wholesale Price ofdrug;cost/day is based on minimum and maximum recommendeddaily dose.

Additional studies are necessary to determine the overall clini-cal and economic implications of olanzapine IM in comparisonwith alternative treatment options.

References available upon request.

Ryan Cello, UCSF PharmD Candidate and Julie DeBoard,PharmD Candidate, Renée Spencer, PhD

According to the Office of National Drug Control Policy,an estimated 898,000 people in the United States chroni-cally used illicit opioids in 2002. Opiate addiction affectspeople in all walks of life and estimated costs are up to 20billion dollars per year. This takes into account cost of treat-ment, lost productivity of employees, crime, healthcare andmany other factors. A recent study showed that only100,000 patients are currently receiving treatment for theirdisease. This is due in part to the limited access to treatmentcenters experienced by these patients.

This limited access to treatment centers helped lead to thepassing of the Drug Addiction Treatment Act of 2000(DATA 2000). The DATA 2000 expands the clinical con-text of medication-assisted opioid addiction treatment by

expanding qualified physicians’ ability to prescribe and dis-pense specific schedule III, IV & V narcotic medicationsin settings other than the traditional opioid treatment pro-gram such as a methadone clinic. This new model for thetreatment of opioid addiction is referred to as “officebased opioid therapy”(OBOT).

Until the passing of the DATA 2000, the main thera-peutic options available for opioid addiction therapywere methadone, levo-alpha-acetyl-methadol (LAAM),and naltrexone. These drugs are used for detoxificationto help alleviate the symptoms of withdrawal while thepatients adjust to a drug free state. They can be contin-ued as part of a long-term treatment program, can be sub-stituted with behavioral therapy or used concomitantlywith behavioral therapy.

Methadone has been used as an effective opiate detoxi-fication treatment for the past 30 years. It has a half life of15-22 hours and the ability to block opiate withdrawal fora duration of 24 hours. Similar to methadone, LAAM hasthe ability to block withdrawal symptoms and has beenfound to be an effective treatment for opiate addiction. Ithas a duration of action of 72 hours and thus only needsto be dosed orally three times a week. Naltrexone is an opi-ate antagonist that can block the effects of opiates by pref-erentially binding to the opiate receptors and displacingany opiates that are bound. Naltrexone has long lasting ef-fects that can last from 1-3 days depending on the dose.Naltrexone is mainly used as an antidote for patients suf-fering from opiate overdose but it can also be used by for-mer addicts to prevent relapse.

The main problem with methadone and LAAM is thatfederal regulations allow only an Opioid AgonistTreatment Program possessing a current, valid certifica-tion from SAMHSA to dispense opioid schedule II drugsin the treatment of opioid addiction. This means that forpatients to get their medications they need to go to a des-ignated opioid treatment program such as a methadoneclinic. Many potential patients have limited access to ad-diction treatment due to the small number of clinics, in-ability of a primary care physician to prescribe addictiontreatment medications and the stigma associated withmethadone clinics.

With the passing of the DATA 2000 physicians nowhave the ability to prescribe schedule II-V drugs for thetreatment of opiate addiction. Both Subutex andSuboxone, schedule III drugs, are now available for usein the treatment of opioid dependence. Suboxone comesas a sublingual tablet that contains buprenorphine HCland naloxone HCl dihydrate at a ratio of 4:1 buprenor-phine:naloxone (ratio of free bases). Subutex is a sublin-gual tablet containing only buprenorphine HCl.

The mu-opioid receptor is involved in causing eupho-ria and analgesia. Naloxone is an antagonist at the mu-opioid receptor. Buprenorphine is a partial agonist at themu-opioid receptor. At low doses it behaves as an opiateagonist but when it is given in high doses it behaves as-both an opiate agonist and an antagonist. Buprenorphine

Buprenorphine & Office BasedOpioid Therapy (OBOT)

Intramuscular Olanzapine ... continued

has a high affinity for the opiate receptor and if it is givenwith heroin or methadone it will displace either from thereceptor.

Suboxone and Subutex come as a 2mg tablet and a 8mgtablet. An 8mg Suboxone sublingual tablet has a half-life =37hours. The naloxone is included in the Suboxone formu-lation to discourage patients from injecting the medica-tion due to the fact that when injected the naloxone isfully absorbed and can lead to acute opiate withdrawal.

In a Cochrane systemic review that evaluated the effectsof buprenorphine maintenance against placebo andmethadone maintenance, it was found that buprenor-phine is an effective intervention for use in the mainte-nance treatment of heroin dependence. This reviewincluded 13 randomized clinical trials with 12 of thembeing double-blind. Although buprenorphine is not su-perior to methadone, in regards to patient retention andsuppression of heroin use, buprenorphine was found tobe statistically superior to placebo at all doses.

The passing of the DATA 2000 allows buprenorphine,a schedule III drug, to be prescribed in a setting otherthan the traditional methadone clinic. Only a qualifiedphysician, which is defined in the DATA 2000 as a physi-cian who is licensed under State law, has DEA registra-tion to dispense controlled substances, has the capacity torefer patients for counseling and ancillary services, willtreat no more than 30 such patients at any one time, andis qualified by certification, training, and/or experienceto treat opioid addiction, can prescribe buprenorphine.Ultimately, the DATA 2000 may improve access to treat-ment for many patients seeking detoxification. References available upon request.

PsychopharmacologyN E W S L E T T E R

Volume 7, Issue 3 September 2004

THIS NEWSLETTER IS SUPPORTED BY UNRESTRICTED EDUCATIONAL GRANTS FROM:

THE BAY AREA PSYCHOPHARMACOLOGY NEWSLETTER

Douglas Del Paggio, PharmD, MPA, Editor2000 Embarcadero Cove, Suite 400Oakland, California 94606-5300

BAY AREA PSYCHOPHARMACOLOGYNEWSLETTER

Editor:Douglas Del Paggio, PharmD, MPA2000 Embarcadero Cove, Suite 400Oakland, California 94606-5300(510) 567-8110 FAX (510) 567-6850email: delpaggio@bhcs.mail.co.alameda.ca.us

Contributors:Alameda County:Richard P. Singer, MDDouglas Del Paggio, PharmD, MPAAlice Myong, PharmD

San Francisco County:Jimmy Jones, MDMary Ann Sullivan, PharmDRenée Spencer, MA, PhDTalia Puzantian, Pharm D

San Mateo County:Celia Moreno, MDBarbara Liang, PharmD

Graphic Designer: Janie Chambers

INSIDE THIS ISSUE

Buprenorphine & Office Based Opioid Therapy (OBOT) . . .2County Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3CME Calendar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Continued on page 2

CONTINUING

MEDICAL EDUCATION

The Bay Area Psychopharmacology Newsletteris now available on the Alameda CountyBehavioral Health Care Services website:http://bhcs.co.alameda.ca.us/ at the top ofthe page in the list of Quick Links.

Nora Tu, UCSF PharmD Candidate and Renee Spencer, MA, PhD

INTRODUCTIONOlanzapine (Zyprexa) is an atypical antipsychotic indicated for

the treatment of schizophrenia and acute mixed or manic episodesassociated with bipolar I disorder. Recently (March 2004), olan-zapine intramuscular (IM) was approved by the FDA for the treat-ment of agitation associated with schizophrenia and bipolar Imania. Agitation associated with neuropsychiatric disorders suchas schizophrenia and bipolar disorder is common and often re-quires treatment. Parenteral administration of antipsychotics isoften favored for controlling acute agitation due to its rapid on-set of action. It is also beneficial when agitated patients refuseto comply with oral medications. In the past, typical an-tipsychotics such as haloperidol and benzodiazepines such aslorazepam were the only available treatment options for acuteagitation. However, typical antipsychotics are often associ-ated with undesirable side effects, including hypotension andextrapyramidal symptoms (EPS). Lorazepam is also associ-ated with certain risks such as lethargy and increased cogni-tive impairment. Ziprasidone (Geodon) IM, approved by theFDA in June 2002, was the first atypical antipsychotic availablein a short-acting intramuscular formulation. Ziprasidone IMhas shown comparable efficacy to haloperidol IM, and was also better tolerated, especially in motor side effects such as EPS.The newly formulated olanzapine IM may be another safe and effective alternative for managing agitation, possibly with amore rapid onset of action and reduced motor and sedating side effects.

CLINICAL PHARMACOLOGY & PHARMACOKINETICSOlanzapine’s antipsychotic activity is believed to be mediated through the combined inhibition of dopamine and serotonin type

2 (5HT2) receptors.1

Olanzapine IM is rapidly absorbed, with peak plasma concentrations occurring within 15-45 minutes. 1The maximum plasma

concentration of olanzapine IM is approximately 5 times higher than that of oral olanzapine at an equal dose. Area under thecurve (AUC) and half-life (t1/2) are similar for IM and oral doses. The half-life of olanzapine ranges from 21 to 54 hours, andthe apparent plasma clearance ranges from 12 to 47 L/hr.

SAFETY AND EFFICACYThe safety and efficacy of olanzapine IM in the treatment of agitation was established in 3 short-term (24 hours of IM treatment)

double blind, placebo-controlled studies in agitated inpatients. Two studies compared olanzapine IM and haloperidol IM inschizophrenic patients (total n=581), and one study compared olanzapine IM and lorazepam in patients with bipolar I disorder(n=201). In all 3 studies, the Positive and Negative Syndrome Scale Excited Component (PANSS-EC), used to determine changesin levels of agitation, was the main measure of outcome. Other measures used included: Agitation-Calmness Evaluation Scale

Intramuscular Olanzapine:Treatment for Acute Agitation

(ACES), Agitated Behavior Scale, and the Cohen-MansfieldAgitation Inventory (for patients with dementia).

In the studies 2,3 comparing olanzapine IM (1-3 injections, ad-ministered at 2.5, 5.0, 7.5, 10.0 mg) with haloperidol IM (7.5mg) and placebo, olanzapine IM exhibited a dose-response

Biological Correlates of PTSDByron Wittlin, MDSeptember 3rd 2004 12-1pm SFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Long-term Management ofSchizophreniaJohn Csernansky, MDSept 24th 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Treatment-Resistant PTSDMark Hamner, MDOct 1st 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Social Anxiety: Diagnosis &TreatmentOwen Wolkowitz, MDOct 29th 2004, 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Legal Issues in PsychopharmacologyDavid Naimark, MD, FAPANov 12th 2004 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433

Treatment of Agitation in DementiaPierre Tariot, MDDec 3rd 2004 12-1pmSFGH 7M30 at 1001 Potrero Avenue(415) 206-3433