Medical Complications of Drug Use
Jeanette Tetrault, MD
Assistant Professor of Medicine
Yale University School of Medicine
Focus of today’s discussion
• Complications of Injection Drug Use (IDU)
– Acute
• Withdrawal
• Bacterial infections: Skin, endovascular
– Chronic
• Hepatitis B
• Hepatitis C
• HIV
– Prevention
– Mortality and drug overdose
Case: 31 yo man presents to ED feeling “sick”
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10 year history of injection heroin use
6 month history of increasing cocaine use
Symptoms - myalgias, weakness, cough
No history of TB or HIV
PE – T 101.2, fresh and old track marks
No cardiac murmur, non-tender abdomen
Labs - WBC 12,000 with normal differential
Urine-trace protein
Should the patient be hospitalized?
• What clinical diagnoses are likely based on this
presentation?
• Which of these diagnoses merit hospitalization?
Presentation of febrile IDUs
• Of 296 febrile IDUs presenting
to urban teaching hospital, 64%
(180) had apparent major
illness:
• Therefore, 36% (103) without
apparent illiness
89% (92) with
minor illness
Abscess 6%
Cellulitis
37%
Endocarditis 6%
Pneumonia
34%
Samet JH, Shevitz A, Fowle J, Singer DE. Am J Med. 1990;89:53-57
11% (11) with
major illness
Diagnoses of patients with occult major illness
Patient
Diagnosis
Bacteremia
1
Infective Endocarditis
Group G β-hemolytic
streptococcus
2
Infective Endocarditis
Staphylococcus aureus
3
Infective Endocarditis
Staphylococcus aureus
4
Infective Endocarditis
Staphylococcus aureus
5
Infective Endocarditis
Staphylococcus aureus
6
Infective Endocarditis
Staphylococcus aureus
7
Infective Endocarditis
Staphylococcus viridans
8
Pneumonia
None
9
Pneumonia
None
10
Disseminated intravascular
coagulation
None
11
Deep venous thrombosis
None
Management of febrile IDUs
• Significant univariate predictors of major illness
– Fever (RR 4.76, 95% CI1.52-14.92)
– Last IDU < 5 days PTA (RR 6.30, 85% CI 1.05-37.79)
– Proteinuria (RR 4.44, 95% CI 1.27-15.5)
• Recommendations for febrile IDUs
– Decision to hospitalize rests on need for follow-up after
blood cultures returned
– If follow-up is not possible, patients should be
hospitalized
Case follow-up
• Tests
– Chest x-ray-normal
– Blood cultures negative after 24 hours
• Assessment/Plan
– Diagnosis-Viral Syndrome
– Patient discharged home
– Referred for substance abuse counseling
Heroin: A brief history
• 1874-first synthesized by an
English chemist
– Diacetyl-morphine
• 1897-resynthsized by Felix
Hoffman working for Bayer trying
to produce codeine
• 1898-1910-marketed as a cough
suppressant and non-addictive
morphine substitute
– Then discovered it was
metabolized to morphine
• 1914 Harrison Narcotics Act
banned sale and distribution
• 1924 became a Schedule 1 drug
Injection drug use
• Lifetime prevalence 1.33% (NSDUH, 2008)
• 425,000 current IDUs
• Medical complications of IDU result from:
• Taking compound of uncertain composition
• Solubilizing compound with a solvent (usually water) that has been
sterilized to a widely-varying degree
• Sterilizing the resulting mixture to a widely-varying degree
• Violating the body’s most effective barrier vs. infection through use of
needle
• Injecting mixture directly into vasculature
Acute complications: Opioid withdrawal
• Severe flu-like symptoms
• Anxiety
• Hyperactivity
• Drooling
• Lacrimation/Tearing
• Rhinorrhea/Runny nose
• Anorexia
• Nausea
• Vomiting
• Diarrhea
• Myalgias
• Muscle spasms
IDU acute infectious complications: Soft tissue
• Cellulitis, abscess, fasciitis: most likely reason
for IDU hospital admission
• Sites: any site of injection
• Organisms: predominantly staph. and strep.
• Antibiotics may fail due to local necrosis of
vessels (especially in those who inject cocaine)
• Drainage, often multiple times, may be
required
IDU acute infectious complications: Endocarditis
• High risk of “right-sided” endocarditis
– “left-sided” still more common
• Usually skin flora
– may be mouth flora from needle-licking
• High degree of suspicion in febrile IDU
(+/- heart murmur)
– Blood cultures
• Infection may be relatively benign or
highly virulent
• Treatment
– Long term antibiotics
– Surgery if valvular destruction, abcess or
cerebral emboli
Samet, Am J Med, 1996
IDU acute infectious complications: Endovascular
• Septic emboli
– Small colonies of bacteria
flick off vasculature (valves,
vessels) into soft tissue/organ
parenchyma
• Metastatic seeding
– Transient bacteremia from
injection can settle in bone,
muscle, joint space etc
Harm reduction for IDUs
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Use clean needles
Use sterile water as solvent
Rotate injection sites
Alcohol wipes on skin
Do not lick needles
IDU chronic infectious complications: Viral
• Hepatitis B
• Hepatitis C
• HIV
Epidemiology of Hepatitis B
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Estimated 1.25 million chronically infected in U.S.
Approximately 300,000 new cases per year
Transmission is blood borne, sexual, or perinatal
Approximately 50% of active injection drug users
have serological evidence of prior exposure to HBV
Natural history of Hepatitis B
• Early disease manifests with symptoms of hepatic
inflammation with elevated LFTs (> 10-20x normal)
• Chronic viral hepatitis manifests as chronic liver
disease with portal hypertension and poor hepatic
synthetic function
• Likelihood of developing chronic infection is related
to age:
– 80 to 90% of infants infected develop chronic disease
– only 2 -10% of infected adults progress to chronic disease
Epidemiology of Hepatitis C (HCV)
• Most common blood-borne infection in the U.S.
• Incidence: 35,000 new cases per year in U.S.
• Seroprevalence studies reveal that approximately 1.8% of
the U.S. population have been infected with HCV
• IDU is the major risk factor for HCV
– 65% of new cases
– 20-50% of chronic infections
– 40-90% of injection drug users (IDUs) have HCV antibodies
National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002 Hepatology. 2002
Nov;36(5 Suppl 1):S3-20
Natural history of HCV
Acute HCV
HCV Antibody +
10-20 years
Resolved
15% to 20%
Chronic HCV
80% to 85%
Stable
85% to 90%
Cirrhosis
10% to 15%
Slowly
progressive
75%
HCC,
liver failure
25% (2% to 4%)
NIH Management of Hepatitis C Consensus Conference Statement. June 10-12,
2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html.
Sexual Transmission of HCV
• Efficiency low
• Rare, but not absent—estimated 0.03-0.6% per year
between long-term monogamous discordant partners—
no change in sexual practices recommended
• Risk amongst those with multiple sexual partners is 1%
per year—barrier methods or abstinence recommended
• Presence of other sexually transmitted diseases
increases risk of transmission
Factors influencing progression of HCV
• Virus
• Behaviors and Environment
– Viral Load
– Alcohol use
– Genotype
– Drug use (licit and illicit)
• Host
– HBV co-infection
– Sex
– HIV co-infection
– Age
– Fatty liver infiltration
– Race
– Iron overload
– Duration of infection
– Genetics
– Immune response
Patients* With HCV infection (%)
Liver Function Tests in HCV
100
80
60
42
43
40
15
20
0
Persistently
Normal ALT
Intermittently
Elevated ALT
Persistently
Elevated ALT
*Patients with ≥ 4 serum ALT level measurements during 25 months of follow-up (n = 1042).
Inglesby TV, et al. Hepatology. 1999;29:590-596.
Treatment milestones in HCV
• RVR= rapid virologic response; week 4
– Absence of detectable HCV quantitative viral load
• EVR= early virologic response; week 12
– cEVR=absence of detectable HCV quantitative viral load
– pEVR=greater than 2 log (10) reduction in HCV viral load
• EOTR=end of treatment response
– Week 48 for genotype 1 and 4 infection or HIV-coinfection
– Week 24 for genotype 2 and 3 infection
• SVR=Sustained virologic response
– Absence of detectable viral load 24 weeks after end of treatment
Treatment of HCV: Pegylated IFN + Ribavirin
• Goal of treatment=SVR
– 42% for genotype 1
– 82% for genotypes 2 and 3
• Side effects
– Pegylated interferon
• Flu-like symptoms, depression,
• 5-10% require discontinuation of therapy
– Ribavirin
• Pancytopenia, hemolytic anemia
IDUs and Treatment of HCV
• 2002 NIH guidelines on treatment of HCV
– Management of HCV-infected IDUs is enhanced by
linkage to drug treatment programs
– Promotes collaboration between HCV experts and
addiction medicine experts
– HCV treatment of active IDU should be considered on a
case-by-case basis
– Active IDU should not exclude patients from HCV
treatment
Patients (%)
Methadone treatment and HCV
100
90
80
70
60
50
40
30
20
10
0
P = .01
76
P = .16
50
56
42
n=
50
50
50
ETR
SVR
Response Outcomes
Mauss S, et al. Hepatology. 2004;40:120-124.
50
Controls (no
IDU for ≥ 5
years)
Patients on
methadone
maintenance
Emerging therapies for HCV: Direct acting
antivirals (DAA)
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
ER lumen
(+) RNA
LD
LD
Translation
NS3/4 and
protease
polyprotein
inhibitors
processing
Boceprevir
Telaprevir
Virion
assembly
LD
Membranous
web
ER lumen
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5B polymerase
RNA
replication
inhibitors
Nucleoside/nucleotide
Nonnucleoside
HIV/AIDS
• A blood-borne retroviral infection caused by the human immunodeficiency virus
(HIV)
• Transmission is through sexual contact, parenteral exposure, and perinatal or
postpartum contact
• 25% of the approximately 40,000 new HIV infections per year are through IDU
• IDUs with HIV are less likely to receive antiretroviral treatment
• IDUs less adherent to antiretroviral therapy, but addiction treatment found to
increase medication adherence
HIV/AIDS treatment
• Standard is at least a three-drug regimen frequently called highly active
antiretroviral therapy (HAART)
• Medication classes:
a)Nucleoside reverse transcriptase inhibitors (e.g., Zidovudine or AZT)
b)Nucleotide reverse transcriptase inhibitors (e.g., Tenofovir or Viread)
c)Non-nucleoside reverse transcriptase inhibitors (e.g., Efavirenz or
Sustiva)
d)Protease inhibitors (e.g., Indinavir or Crixivan)
e)Membrane fusion inhibitor (e.g., enfuvirtide or Fuzeon or T-20)
f) Newer Classes of medications (e.g., integrase inhibitors, CCR5
inhibitors)
HIV seroconversion
• Reduced by opioid agonist treatment among IDUs
• Metzger, 1993:
2 cohorts of patients
– 103 out-of-treatment intravenous opiate users
– 152 subjects receiving methadone treatment
HIV antibody conversion, 18-months
– 22% of those out-of-treatment
– 3.5% of those receiving methadone treatment
Metzger DS, et al. Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: An 18 month prospective
follow up. JAIDS. 1993
Methadone and HIV Prevention
• Methadone patients report less needle and
syringe sharing
• Methadone patients are 3-6 times less likely
to become HIV positive when compared to
out-of-treatment heroin users, including the
population who continues to use drugs
De Castro S, Sabate E. Adherence to heroin dependence therapies and human immunodeficiency virus/acquired
immunodeficiency syndrome infection rates among drug abusers.
Clin Infect Dis. 2003 Dec 15;37 Suppl 5:S464-7
Buprenorphine and HIV prevention
• Buprenorphine is a partial opioid at the µ-opioid
receptor, treatment option for opioid dependence
• Longitudinal analysis of primary care patients on
buprenorphine†
– N=166 patients
– Decreased risk behaviors between baseline and 24
weeks
• IDU: 37% to 7%, p<0.001
• Sex while high: 64% to 15%, p<0.001
† Sullivan LE et al. Buprenorphine/naloxone treatment in primary care is associated with decreased HIV behaviors.
JSAT. 35: 87-92. 2008.
Buprenorphine and HIV treatment
• MANIF cohort*
– N=164 pts on HAART; 32 on bup, 113 prior IDU, 19 active IDU
– Those on buprenorphine were more likely to be adherent to HAART than
those with active IDU (OR 5.1 95%CI 1.3-20.1)
– 6 mo follow-up no difference in CD4 and VRL between patients on bup
and prior IDU
• HIV+, opioid dependent patients treated with bup†
– N=16 patients
– + Utox 100% to 16% at 3 mos
– No difference in HIV parameters
*Moatti JP, et al. Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine
drug maintenance treatment. AIDS. 14(2) :151-5, 2000.
† Sullivan, LE et al. A trial of integrated buprenorphine/naloxone and HIV clinical care. Clinical infectious diseases. 43 suppl:184-190, 2006.
Methadone interactions with antiretrovirals
• Nucleoside reverse transcriptase inhibitors
– Methadone increases AZT through inhibition of
glucoronidation
– May increase side effects of AZT
• Non-nucleoside reverse transcriptase inhibitors
– Efavirenz decreases methadone levels
– May cause withdrawal
• Protease Inhibitors
– No clinically significant interactions
Buprenorphine interactions with antiretrovirals
• Nucleoside reverse transcriptase inhibitors
– No clinically significant interactions
• Non-nucleoside reverse transcriptase inhibitors
– Efavirenz decreases buprenorphine levels
– Not clinically significant
• Protease inhibitors (P450 3A4)
– Atazanivir increases buprenorphine levels
– May cause sedation
Routine screening for patients with addiction
• Viral Hepatitis A, B, C: Screening antibody tests and liver
enzymes
• HIV screening yearly
• Tuberculosis: Annual screening with PPD and/or chest xray
• Syphilis: Annual VDRL or RPR
• Cervical cancer: Yearly screening PAP smear, more
frequent (q6month) in those with prior abnormalities
• Immunizations: pneumovax, flu, Tdap, twinrix
Mortality as a result of drug overdose
• Death from overdose is rare but may have spikes of increased
incidence due to increased purity of illicit drugs
• Particularly vulnerable times
– Release from prison
– Discharge from drug treatment
• Respiratory depression is a factor BUT CNS depression is often
the cause
– Mixture of CNS depressants have additive effect; mixture
of opioids/stimulants has complex interaction
Other factors affecting mortality
• Harder to quantify and usually ignored
– Poor preventative care, uninsurance/underinsurance,
fragmented healthcare
– Poor health literacy
– Poverty, malnutrition
– Co-occuring and often poorly recognized/treated mental
illness
Summary
• Patients with addiction frequently have co-morbid medical
conditions, especially infectious diseases
• Important to screen for these disorders, and to provide
treatment and prevention interventions
• Monitor patients for interactions between medications used
to treat addiction and medications used to treat chronic
diseases
• Linkage of addiction treatment with medical treatments and
prevention for co-morbid disorders can enhance medical
treatment outcomes
Thank you!