Journal Update September 2003

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Journal UpdateSeptember 2003

• Michael Rotblatt, MD
• Soma Wali, MD

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Topics Today

• Tx of opiate addiction
• HTN, proteinuria and non-diabetic kidney disease
• Pharmaceutical Update

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Case 1

• 31 y.o. M supermarket manager is admitted to your
  ward service for LE cellulitis
• Upon questioning, he admits to injecting IV
  heroin
• Hed like to quit the habit, but doesnt want the
  stigma of going to a drug abuse clinic
• He asks if theres anything you can do to help
  him, as hes heard of a new drug that can be
  prescribed by general physicians for drug detox

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Background

• 1914 Harrison Narcotic Drug Act
• Illegal for physicians to prescribe narcotics for
  the tx of opioid dependence
• Exception methadone (and LAAM) through regulated
  programs (Schedule II triplicates)
• 2000 Drug Addiction Treatment Act
• Allows Schedule III, IV, or V narcotics (that
  have been FDA approved for such use) to be
  prescribed for medically supervised detox
  (tapering) or maintenance
• Oct. 2002
• FDA approved buprenorphine and the combination
  buprenorphine/naloxone (DEA III) for detox or
  maintenance

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Background

• Buprenorphine narcotic for mod-severe pain
• partial mu-receptor agonist
• max effective dose 60-70 mg methadone
• mixed agonist/antagonist
• Mean half-life 36 hrs
• Buprenorphine naloxone (narcan)
• reduces drug diversion to IVDU (crushing and
  injecting IV) since naloxone IV -- withdrawal sxs

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Fudalla et al. Office-Based Treatment of Opiate
Addiction with a SL-Tablet Formulation of
Buprenorphine and Naloxone. NEJM Sept. 4, 2003
349949-58

• Multicenter, randomized, placebo-controlled trial
  to assess the safety and efficacy of SL
  buprenorphine (and buprenorphine/naloxone) in an
  office-base setting

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Methods

• Enrolled adults with opiate dependence (DSM-IV)
• Exclusions
• Pregnant, nursing, abnl liver labs, Axis I Psych
  d/o, methadone/LAAM/naltrexone w/in 2 wks
• Study visits in a physicians office
• Remote from drug detox/maintenance clinics

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Methods

• DBPCT x 4 wks
• Clinic visits daily (M-F) - given pill on that
  day
• Pts randomized 3 groups
• buprenorphine 16mg SL qd
• buprenorphine 16mg/naloxone 4mg SL qd
• Placebo qd
• Open-label safety phase x 1 yr
• Clinic visits daily x 2 wks, then up to a 10 dy
  supply
• buprenorphine/naloxone - up to 24/6 mg qd

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Outcome Measurements

• DBCT
• Primary outcomes
• of opiate - urine tests (urine samples 3x/wk)
• Subjects self-reported cravings for opiates (100
  pt. VAS)
• Secondary outcomes
• Overall status by subject and physician
• VAS - worse - no change - better
• of urine tests - for other drugs of abuse
• Subject retention, adverse events...
• Open-Label (urine tests results available)
• Outcomes labs, PE, adverse events

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Results

• DBCT
• Goal to enroll 384 subjects
• After 323 subjects enrolled and 243 (82)
  completed the trial, study terminated early
• Primary outcomes - urine test cravings
• Buprenorphine 20.7 62 -- 33
• Bupren/naloxone 17.8 62 -- 30
• Placebo 5.8 65 -- 55
• (p
• Secondary outcomes
• Better overall status with study drugs, well
  tolerated

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Results

• Open-Label - buprenorphine/naloxone
• 472 subjects assessed for safety
• 261 6 months
• Most serious AEs
• Increases in ALT, AST, LDH in 10 subjects
• 8/10 with viral hepatitis
• urine tests - for opiates
• 35 ---- 67 (4 weeks -- 1 year)

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Authors Conclusion

• Both buprenorphine alone and buprenorphine
  combined with naloxone provide safe and effective
  treatment of opiate-addicted persons in an
  office-based setting

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Study Limitations

• DBCT biased for poor results (opiate-free)
• Short duration (one month)
• Fixed dose (individual titration not permitted)
• Clinicians blind to urine test results
• Biased for better results
• Expertise and resources of the study
  investigators (not usual clinic physicians)
• Did not mimic current use for buprenorphine
  prescribing (
  needs
• Daily (DBCT) or

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Study Limitations

• Buprenorphine vs. placebo ???
• Better study
• Buprenorpine vs. methadone

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Our Bottom Line

• Buprenorphine acts, as expected, like any opioid
  narcotic in opiate addicted persons
• Used SL with naloxone, it appears safe and
  somewhat effective for opiate addicts in
  outpatient clinics
• More important than these study results is the
  change in recent laws and availability of this
  drug for physicians

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Perspective

• 17 wk study in 270 pts, buprenorphine SL
  methadone or LAAM NEJM 20003431290
• French experience
• Approved methadone in 1993 and buprenorphine in
  1996 by any MD -- encouraged buprenorphine
  because harder to OD and easier to detox
• By 2001, 80,000 French patients taking
  buprenorphine, most by general physicians
• Deaths from heroin ODs dropped nearly 80 from
  1994 to 1999 (566 -- 118)
• 2 yr study 900 pts txd by general
  practitioners found improvements in social status
  and decrease in drug abuse

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Perspective

• Concerns about diversion and abuse --
• DEA schedule V (1985) -- schedule III
• Limit the number of patients each physician can
  treat
• combination with naloxone
• Drug Addiction Treatment Act of 2000
• Requires that physicians undergo 8 hrs authorized
  training in the use of buprenorphine
• Unless already certified in addiction medicine
• Register with the SAMHSA
• Tx
• As of late June, 3000 physicians have undergone
  training, only 1900 had applied

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Perspective

• Anecdotally
• Patients must be free of opiates x 1-2 dys to
  avoid precipitating withdrawal rxns
• Dosing should be individualized - pts may even
  titrate own doses
• Buprenorphine (Subutex(R)) 2, 8 mg SL tabs
• With 0.5, 2 mg of naloxone (Suboxone(R))
• Cost 300/month (vs. 30/month for methadone)
• More information
• Substance Abuse and Mental Health Services
  Administration (SAMHSA)
• Http//buprenorphine.samhsa.gov

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Case

• 31 y.o. supermarket manager who is a heroin user,
  asking for your help in the clinics with his drug
  dependence
• Is this patient like those in the study?
• Can only prescribe buprenorphine SL if
• Taken an authorized 8 hr training course
• Registered with SAMHSA
• Formulary drug

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Case 2

• 42 year old male with h/o HTN, CKD (Cr 1.7),
  and no hx of DM presents to your office
• Pt states that he is very concerned about his
  kidney function and will try anything to make
  sure he does not go on HD
• He monitors his BP daily and wants to know how
  low should his BP be in order to avoid
  progression of his kidney disease.

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Background

• In US approximately 5.6 million adults have
  Chronic Kidney Disease (CKD).
• Many also have HTN, either as a cause or
  complication of kidney disease.
• HTN and proteinuria occur in most pts with CKD
  and are risk factors for faster progression of
  Kidney Disease.

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Definition of CKD

• Reduced excretory fxn (estimated GFR ml/min/1.73 m2)
• Cr approximately 1.5 in men
• Cr approximately 1.4 in women
• Presence of urinary findings
• Albuminuria 300 mg/d, or
• Ratio of 200 mg Alb/g of Cr

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Goal of Aggressive BP Management

• Slow deterioration of renal function
• Prevent cardiovascular disease
• However Kaplan et al (Lancet, 1998) and others
  reported that excessive lowering of BP is
  associated with increased risk for cardiovascular
  disease.
• The role of ACE-I in treatment of HTN
• Agent of choice for patients w/ diabetes
• Agent of choice for patients w/ CHF
• Reduces urinary protein excretion
• Reduces progression of CKD in diabetic and
  non-diabetics

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JNC-7 Guidelines for Pts with CKD

• Aggressive treatment of HTN to target
• BP
• BP 1g/d
• Does not address whether the target BP should
  vary depending on severity of Kidney Disease.
• How low should we go?
• Can we go too low?

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Jafar et al, Progression of Chronic Renal
Diseases. The role of BP Control, Proteinuria,
and ACEIAnn Int Med, August 19, 2003

• Meta-analysis
• Purpose
• To determine the levels of BP and urinary protein
  excretion associated with the lowest risk for
  progression of CKD
• In non-diabetics receiving anti-hypertensive
  therapy (ACEI and non-ACEI therapies)

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Method and Study Design

• Meta-Analysis conducted by the ACEI in
  Progressive Renal Disease (AIPRD) study group
• Searched the English language Medline database
  for reports evaluating the effects of ACEI on KD
  between 1977 and 1999

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Methods

• Study inclusion criteria
• RCTs with a minimum of one year follow-up.
• Compared effects of antihypertensive regimens
  that included ACEI to regimens that did not
  include ACEI (or ARBs).
• Concomitant anti-hypertensive meds used in both
  groups to achieve a target BP
• All pts followed at least once / 3 months for
  first year and then every 6 months thereafter.

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Methods (cont.)

• Patient inclusion criteria
• HTN
• Decreased renal function
• Patient exclusion criteria
• Renal failure (ESRD), obstructive uropathy, RAS
• Type I diabetes, Type II diabetes (excluded
  later)
• CHF
• History of transplantation
• History of allergy to ACEI
• Pregnancy
• Active systemic diseases

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Final Database

• Final Database included
• 11 RCTs of ACEI used to slow progression of KD.
• 1,860 pts with non-diabetic KD
• 22,610 visits
• Mean during of follow-up was 2.3 years
• Range of 1.4 - 3.2 yrs

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Primary Outcome

• Kidney Disease Progression (KDP) defined as
• A two fold increase in serum Cr concentration
  from baseline, or
• Development of Kidney Failure (KF) defined as
  initiation of long term dialysis therapy

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Results for Anti-Hypertensives

• 311 pts (16.8) experienced KDP (doubling of
  serum Cr or KF) in 2.3 years.
• 124 (13.2) in ACEI group
• 187 (20.5) on non-ACEI drugs
• A total of 176 (9.5) developed KF
• 70 (7.4) in ACEI group
• 106 (11.6) on non-ACEI drugs
• (Differences are stat. sign. at p0.001)

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Results for BP

• SBP was more related to KDP than DBP
• SBP 130 --- increased risk for KDP RR
  from 1.83 (SBP 130-139) to 3.14 (SBP 160)
• SBP 110-129 --- lowest risk for KDP
• SBP increased risk for KDP (RR
  2.48)
• After adjustment for different levels of SBP and
  urine protein excretion, the risk for KDP was
  still lower in patients assigned to ACEI

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Results for Urine Protein Excretion

• The lowest RR for KD progression was at urine
  protein excretion
• 1-2 g/d, RR 1.67
• 2 g/d, RR 2.25
• 6 g/d, RR 4.77

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Results for Urine Protein Excretion in relation
to SBP

• Urine protein
• RR 1 for SBP 110-159
• RR 2 for SBP 160
• Urine protein 1 g/d
• RR 1 for SBP 110-129
• RR 4.7 for SBP 130-139
• RR 8 for SBP 160

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Authors Conclusion

• SBP 110-129 associated with lowest risk.
• SBP
• Urine protein excretion lowest risk of KDP
• After adjustment for SBP and urine protein
  excretion, the risk of KDP was lower in pts
  assigned to ACEI therapy

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Limitations of Study

• Usual weaknesses of meta-analyses
• e.g., Combining heterogeneous groups
• Did not include newer studies after 1999
• Blood pressures and protein excretions only a few
  times per year (single time points)
• Did not address ARBs

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Perspective

• ACEI useful in non diabetic pts w/ CKD
• Some patients have partial reduction in
  proteinuria w/ ACEI (Kidney Int 2003)
• Recent trial suggests added clinical benefits of
  combining ACEI and ARB even with SBP of
  (Lancet 2003361117)
• Systolic HTN in the Elderly data (Young, J Am Soc
  Nephrol 200213) SBP is more strongly
  associated with KDP than DBP
• Animal studies have also shown a higher risk of
  KDP with SBP

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Case 2

• 42 y.o. M with HTN and non-diabetic CKD wants to
  know how low should his BP be in order to avoid
  KD progression.
• Is this pt like those in the MA?
• Bottom Line
• Start ACEI if pt is not on it.
• Target SBP ideally between 110 and 130.
• Consider urine protein measurements periodically
  (urine dipstick -- alb/Cr ratio)
• Aim to reduce proteinuria to
• Target SBP and not DBP

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Pharmaceutical Update

• New drugs and pharmaceutical news of interest to
  internists

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Ectasy toxicity

• 3,4-Methylenedioxymethamphetamine (MDMA)
• Chemically similar to mescaline and amphetamine
• Safe recreational drug?
• Cases of severe toxicity -- death
• Cardiovascular collapse
• Hepatic
• Hyperpyrexia
• Cerebral - szs, edema/hemorrhage, hyponatremia
• www.clubdrugs.org (National Institute on Drug
  Abuse)

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New Drugs

• Alfuzosin, extended release (Xatral(R))
• alpha1-blocker for BPH
• Dose 10 mg daily
• Potential SEs dizziness, HA, fatigue
• Aprepitant (Emend(R))
• New anti-emetic for Cancer chemo
• First P/neurokinin 1 (NK1) receptor antagonist
• Use with steroid and 5-HT3 inhibitor (dexam
  Zofran)
• Lowers incidence of acute and delayed N/V
• Cost 300 many drug intxs (liver Cyt P450)

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Potential Patent Expirations - 2003

• Amlodipine (Norvasc)
• Fosinopril (Monopril)
• Bupropion (Wellbutrin)
• Benazepril (Lotensin)
• Paroxetine (Paxil)
• Gabapentin (Neurontin)
• Ciprofloxacin (Cipro)

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Counterfeit Drugs

• New major problem in the U.S.
• Many high-priced brands found to contain
  diluted or no active substances
• Lipitor, Procrit/Epogen, Combivir, Retrovir,
  Viagra...
• Most are imported from Asia, South America, etc
• Repackaged to look like U.S. labels

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Viagra(R) competition

• Vinarol all natural herbal dietary supplement
• FDA recalled product...contains sildenafil
• Vardenafil (Levitra(R)) and tadalafil (Cialis(R))
• New phosphodiesterase type 5 inhibitors
  sildenafil
• Available in other countries.anticipate FDA
  approval
• Viagra chewing gum?
• Wm. Wrigley Jr. Co. has a patent to manufacture
  sildenafil gum to treat ED
• Pfizers patent on Viagra(R) doesnt expire until
  2011
• Reportedly has no plans to license the drug to
  Wrigley
• Double your pleasure, double your fun

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To download this lecture go to

• www.uclaSFVP.org/lectures.htm