Passaro DJ, Werner SB, McGee J, Mac Kenzie WR, Vugia DJ. Wound Botulism Associated With Black Tar Heroin Among Injecting Drug Users. JAMA. 1998;279(11):859-863. doi:10.1001/jama.279.11.859
From the Division of Communicable Disease Control, California Department of Health Services, Berkeley (Drs Passaro, Werner, and Vugia and Mr McGee), and the Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, Calif (Dr Passaro), and the Division of Field Epidemiology, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, Ga (Drs Passaro and Mac Kenzie). Dr Passaro is now with the Division of Infectious Diseases and Geographic Medicine, Stanford University Medical Center. Dr Mac Kenzie is now with the Division of Parasitic Diseases, Centers for Disease Control and Prevention.
Context.— Wound botulism (WB) is a potentially lethal, descending, flaccid, paralysis
that results when spores of Clostridium botulinum
germinate in a wound and elaborate neurotoxin. Since 1988, California has
experienced a dramatic increase in WB associated with injecting "black tar"
heroin (BTH), a dark, tarry form of the drug.
Objective.— To identify risk factors for WB among injecting drug users (IDUs).
Design.— Case-control study based on data from in-person and telephone interviews.
Participants.— Case patients (n=26) were IDUs who developed WB from January 1994 through
February 1996. Controls (n=110) were IDUs newly enrolled in methadone detoxification
programs in 4 counties.
Main Outcome Measures.— Factors associated with the development of WB.
Results.— Among the 26 patients, the median age was 41.5 years, 15 (58%) were
women, 14 (54%) were non-Hispanic white, 11 (42%) were Hispanic, and none
were positive for the human immunodeficiency virus. Nearly all participants
(96% of patients and 97% of controls) injected BTH, and the mean cumulative
dose of BTH used per month was similar for patients and controls (27 g and
31 g, respectively; P=.6). Patients were more likely
than controls to inject drugs subcutaneously or intramuscularly (92% vs 44%, P<.001) and used this route of drug administration more
times per month (mean, 67 vs 24, P<.001), with
a greater cumulative monthly dose of BTH (22.3 g vs 6.3 g, P<.001). A dose-response relationship was observed between the monthly
cumulative dose of BTH injected subcutaneously or intramuscularly and the
development of WB (χ2 for linear trend, 26.5; P<.001). In the final regression model, subcutaneous or intramuscular
injection of BTH was the only behavior associated with WB among IDUs (odds
ratio, 13.7; 95% confidence interval, 3.0-63.0). The risk for development
of WB was not affected by cleaning the skin, cleaning injection paraphernalia,
or sharing needles.
Conclusions.— Injection of BTH intramuscularly or subcutaneously is the primary risk
factor for the development of WB. Physicians in the western United States,
where BTH is widely used, should be aware of the potential for WB to occur
AN ESTIMATED 80000 Americans, including 18000 Californians, inject illicit
drugs.1 Compared with the general population,
injecting drug users (IDUs) are at increased risk for disease and death2- 6
and use a disproportionate amount of medical resources.7,8
Soft tissue infections are a particular problem.9- 11
In 1994, the California Department of Health Services (CDHS) noted an
increasing number of cases of wound botulism (WB), an unusual soft tissue
infection. Botulism is best known as a potentially lethal paralytic disease
that results from ingestion of preserved food containing preformed botulinum
toxin. Wound botulism is a clinically similar syndrome of flaccid, symmetric,
descending paralysis that results when spores of Clostridium
botulinum, an obligate anaerobe, are inoculated into a wound or other
devitalized tissue.12 After gaining access
to this relatively anaerobic environment, the spores germinate and elaborate
the most potent toxin known.13 Historically,
the implicated wound has been a crush injury or other gross trauma to an extremity.14 The first reported case of WB associated with injecting
drug use occurred in 1982 in New York City.15
All forms of botulism are reportable diseases in California. Since 1988,
the year of California's first reported WB case associated with injecting
drug use, the number of WB cases has increased dramatically, totaling 49 from
1988 through 1995; 46 of these cases occurred in IDUs, nearly all of whom
injected primarily heroin. In each case, the same type of heroin was used:
"black tar" heroin (BTH), a black, gummy form of the drug that usually is
synthesized in makeshift factories adjacent to opium poppy fields in several
We performed a case-control study to compare IDUs who developed WB with
other heroin users to identify risk factors associated with the disease.
Case patients (patients) were IDUs who developed laboratory-confirmed
WB from January 1, 1994, through March 1, 1996. All CDHS case records since
1994 were reviewed, and current telephone numbers and addresses of patients
were obtained, generally through hospital records or by contact tracing. Telephone
or in-person interviews were conducted directly with each patient. Patients
unable to speak because of ongoing mechanical ventilation provided written
responses to in-person interviews conducted by nursing staff. Patients without
access to a telephone were interviewed in person by staff of the Local Assistance
Branch, CDHS, Sacramento, Calif.
Controls were persons newly enrolled in 1 of 4 methadone detoxification
programs in geographically and ethnically distinct cities in California (Oakland,
Los Angeles, San Jose, and Stockton) during March through May 1996. Recruitment
strategies for controls varied by clinic. At the Los Angeles clinic, 25 consecutive
patients were enrolled in the study by the clinic intake supervisor. At the
Oakland, Stockton, and San Jose clinics, study investigators visited each
of these 3 on 3 nonconsecutive mornings. Each detoxification program patient
who received methadone was asked to participate in the study and was offered
a meal voucher to encourage participation. Before interviews, educational
flyers about the study and about WB associated with injecting drug use (ie,
"shooter's botulism") were distributed at the clinics; these flyers warned
users of the local WB epidemic among IDUs and explained warning symptoms but
did not discuss hypotheses about the causes of shooter's botulism. After each
interview, participants were given verbal and written information about shooter's
Because our selection of methadone clinic study sites was not random
and to examine whether our control group was representative of California
methadone clinic attendees, we also compared baseline patient characteristics
of our control group with those of a reference group. The reference group
consisted of all enrollees in methadone detoxification or maintenance programs
during 1994 or 1995 from the 17 California counties that have reported WB
Patients were questioned about baseline personal characteristics and
34 drug purchasing, storing, and using practices in the month before developing
WB; controls were asked identical questions about drug-related practices in
the month before starting detoxification, including frequency and quantity
of all drugs injected; frequency and method of cleaning needles and syringes;
frequency of needle sharing; source of water or other solvent used for dissolving
heroin; type of apparatus used for heating the heroin-water mixture; whether
cotton balls or cigarette filters (eg, "cottons"), through which the heroin
mixture is drawn into the syringe, were stored and reused; frequency and type
of skin cleansing before injection; which body sites were used for injection;
and injection technique (intravenous vs intramuscular vs subcutaneous). Participants
were also asked about their recent medical history and how frequently they
developed soft tissue abscesses. Each participant estimated the quantity of
drugs he or she used by stated drug weight at point of purchase. When this
was not possible, quantities were estimated by dollar amounts, which were
converted to weights using the costs most frequently cited by study participants:
$80 per gram of heroin and $100 per gram of cocaine.
Bivariate analyses were performed by using the Fisher exact test or
the Mantel-Haenszel χ2 test (with the Yates correction) for
discrete variables and the Student t test or the
Wilcoxon 2-sample test for continuous variables. Since 34 practices and characteristics
were assessed in the bivariate analyses, the Bonferroni correction was used
to provide a stringent test of significance. Therefore, bivariate associations
were judged significant only if P<.002 (ie, 0.05/34).
Dose-response relationships were assessed using the χ2 test
for linear trend (Epi Info 6.02, Centers for Disease Control and Prevention,
Atlanta, Ga). Multivariable analyses were performed by applying backwards-elimination
logistic regression to all variables associated with a significance level
of P<.2 in the bivariate analysis; likelihood
ratio χ2 statistics were compared to assess the goodness of
fit of increasingly parsimonious multivariable models.17
Because controls were clustered by county, robust (Huber/White/sandwich) estimators
of variance were used to calculate SEs in the multivariable analyses (Stata
5.0, Stata Corp, College Station, Tex). Analyses involving needle-exchange
programs were restricted to patients and controls from Alameda, Los Angeles,
San Joaquin, and Santa Clara counties. All comparisons were 2-tailed.
A total of 35 cases of laboratory-confirmed WB associated with injection
drug use occurred in California during the 26-month study period. Of these
35 patients, all but 2 required lengthy hospitalization; all but 5 required
mechanical ventilation. Of the 34 cases in which botulinum toxin typing was
performed, 30 (88%) were caused by botulinum toxin type A and 4 (12%) by type
B. The case participation rate was 74%; 5 (45%) of 11 patients diagnosed in
1994 and 21 (87.5%) of 24 patients diagnosed after January 1, 1995, were interviewed.
Seven patients could not be located despite repeated attempts, and 2 refused
to participate. Control participation rates varied by study site between 50%
and 80% but were not precisely determined because not all potential controls
could be enumerated at all sites.
No blacks and no persons infected with the human immunodeficiency virus
(HIV) developed WB during the study period; the HIV status of controls was
not documented. Patients were less likely than controls and the reference
group to be non-Hispanic black and more likely to be non-Hispanic white and
to be female, although these demographic trends did not reach statistical
significance. Baseline characteristics were otherwise similar between groups
Of 34 drug purchasing, storing, and using practices analyzed, the behavior
most strongly associated with the development of WB was injecting BTH subcutaneously
or intramuscularly (skin-popping) rather than intravenously (Table 2). A total of 33 of 35 patients reported this route of BTH
administration at least occasionally. One of the 2 exceptions was an intravenous
amphetamine user who insisted that she had never skin-popped, never used BTH,
and never shared paraphernalia with BTH users. The other exception was a patient
who reported injecting BTH but only intravenously.
The total quantity of BTH used monthly by patients and controls was
similar, but the amount that was injected subcutaneously or intramuscularly
was greater among patients than among controls (mean, 22.3 vs 6.3 grams; P<.001). A dose-response relationship was observed between
the monthly dosage of BTH injected subcutaneously or intramuscularly by quartile
and the risk of developing WB (χ2 for linear trend=26.5; P<.001). This dose-response relationship remained when
analysis was limited to persons who reported injecting BTH subcutaneously
or intramuscularly (χ2 for linear trend=4.1; P=.04).
Patients reported having more abscesses that received medical treatment
in the previous year than controls (Table
2). Although cleaning the skin before injection may have protected
against developing soft tissue abscesses (P=.07,
data not shown), cleaning the skin before injection or cleaning syringes between
injections did not protect against developing WB. Using needle-exchange programs
did not protect against WB, and sharing injection paraphernalia was not associated
with the disease.
In the final (parsimonious) multivariable model, injecting BTH subcutaneously
or intramuscularly (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.0-63.0; P=.001), sex, and race were the only factors associated
with WB. Hispanic and non-Hispanic whites had an increased risk of WB (OR,
undefined; P<.001) and women had a nonsignificant
increased risk of WB (OR, 2.2; 95% CI, 0.8-5.9; P=.13).
To better quantify the relationship between BTH dose and risk for illness,
race- and sex-adjusted ORs were calculated for quartiles of cumulative BTH
dose injected subcutaneously or intramuscularly per month. When compared with
IDUs who denied injecting BTH subcutaneously or intramuscularly, the odds
of developing WB were 6-fold higher among "occasional" subcutaneous or intramuscular
injection users (whose dosage was in the lowest quartile, $20-$480 of BTH
per month) and 25-fold higher among "heavy" users (whose dosage of drug injected
subcutaneously or intramuscularly was in the highest quartile, $2000-$6300
of BTH per month) (Figure 1).
From 1951 through 1995, 68 cases of WB were reported to CDHS. An average
of 0.49 WB cases per year were reported from 1951 through 1987; 2.25 cases
per year were reported in 1988 through 1991, 3 cases in 1992, 4 in 1993, 11
in 1994, and 23 in 1995.18 From 1988 through
1995, only 2 WB cases among IDUs were reported from outside California, and
they occurred in Arizona (Foodborne and Diarrheal Disease Branch, Centers
for Disease Control and Prevention, unpublished data, 1996).
This study confirms that the ongoing epidemic of WB in California is
strongly associated with subcutaneous or intramuscular injection (skin-popping)
of BTH and provides evidence to suggest that C botulinum contamination of BTH is not the result of specific drug storage or
other using behaviors among IDUs. Although intravenous injection of heroin
provides a stronger initial "high," "skin popping" is favored by users reluctant
to inject intravenously, who desire to avoid telltale "track marks," or for
whom venous access is difficult because of obesity or the scarring of veins
from repeated use. Black tar heroin was the only drug that patients with WB
Black tar heroin was introduced to US drug users in the 1970s and slowly
gained market share from traditional white heroin because Central and South
American suppliers were able to develop dominant distribution networks and
because initially BTH was cheaper and more potent (up to 50% by weight diacetylmorphine).
Since the late 1980s, BTH has become the predominant form of heroin in the
United States west of the Mississippi River. In 1993, 20 of 21 samples of
California heroin purchased by undercover agents of the US Drug Enforcement
Agency were BTH.19 At present, heroin is highly
impure and contains contaminants (by-products of the manufacturing process),
adulterants (chemicals such as methamphetamine, strychnine, or xylocaine),
and diluents (inert materials, such as dextrose, that are used to "cut" heroin,
providing bulk and weight and increasing the distributors' profit margin).
The tarry color and consistency of BTH has led to the use of unusual diluents,
including ground paper fiber soaked in black shoe polish and, according to
anecdotal reports, dirt.
Our study was not designed to determine at which step in heroin production
and distribution contamination was most likely to occur. However, there are
several reasons to suspect that contamination occurs during "cutting." First,
the last step in the conversion of opium to BTH involves boiling the product
with a strong acid at 150°C for several hours, which should destroy even
heat-resistant C botulinum spores. Therefore, contamination
before or during this step is unlikely to result in a contaminated final product.
Second, during detailed interviews, all 26 patients denied adding other substances
or solvents or using unusual water sources when preparing drugs for injection
(2 controls reported occasionally using beer or wine as a solvent). Therefore,
inadvertent contamination of heroin by individual users seems unlikely to
be the source of C botulinum spores. Third, frequency
of skin cleansing before injection and the type of cleanser used were not
associated with WB, and the quantity of BTH used was a more important factor
than the frequency of use. Therefore, skin contamination with C botulinum appears unlikely to be a major source of this epidemic.
Fourth, the frequency of using new paraphernalia, the frequency and method
of cleaning old paraphernalia, and the sharing of paraphernalia were not associated
with WB. Therefore, spread of WB via fomites or blood is unlikely to be a
factor in this epidemic. For these reasons, we suspect that BTH is most likely
being contaminated when diluted (eg, possibly with soil) after manufacture
or during distribution.
Fundamental questions about this outbreak remain unanswered and probably
reflect incomplete understanding of heroin distribution. For example, the
reason that the location of cases (Figure
2) was spread throughout California yet essentially spared the rest
of the western United States (where BTH is also distributed) is unexplained,
although this pattern is consistent with contamination of BTH during in-state
distribution. The lack of cases of WB occurring among black IDUs is also unclear.
Drug enforcement officials hypothesize that distrust between black IDUs and
suppliers of BTH manufactured by smaller, less experienced producers and distributors
(which might be more highly contaminated) has minimized the use of this type
of BTH among black IDUs.
Reported cases of WB may represent only a small fraction of this epidemic.
Nearly all patients diagnosed as having botulism in California are described,
because botulinum antitoxin is available to California physicians only through
CDHS. However, botulism is a rapidly progressive disease and persons with
limited access to care or who delay seeking health care may be dying outside
the hospital. In these circumstances, the diagnosis of WB could be missed.
For example, if postmortem examination revealed detectable serum opiate levels,
an IDU might be presumed to have died from an overdose. In addition, there
have been several instances in which diagnosis of WB has been delayed despite
consultation with neurologists and infectious disease specialists; a subset
of persons with WB may have been diagnosed as having another neuromuscular
Unlike the more widely publicized infectious complications of drug injection
eg, HIV infection and viral hepatitis B, WB is not contagious. In our study,
risk of disease was not associated with markers of exposure to other IDUs
(eg, frequency of sharing needles). Although 3 clusters of WB involving pairs
of "shooting partners" (persons that use drugs together) have been reported,
in all 3 episodes the partners had used the same heroin (S.B.W., unpublished
The CDHS has been unable to procure BTH samples large enough to adequately
test for C botulinum. Furthermore, the samples obtained
have not been closely linked to BTH samples thought to have caused illness.
Accordingly, our suspicion that BTH contains botulism spores remains unproven.
However, we have cultured C botulinum from the internal
surface of a syringe used by a patient with WB, and we have also cultured
related Clostridia species from BTH samples belonging
to other patients with WB.19
We do not know the source of C botulinum spores
contaminating BTH. However, our findings suggest that BTH is contaminated
before sale to IDUs and that simple measures, such as cleaning the skin before
injection and cleaning syringes, are unlikely to prevent WB.
The CDHS has taken several steps to make drug users, public health officials,
and physicians aware of this growing problem. In October 1995, informational
packets containing both technical and lay fact sheets were sent to every public
health jurisdiction in California for distribution to emergency departments,
needle-exchange programs, and methadone clinics. A report of the outbreak
has been published.16 Education of IDUs and
clinic staff was also provided to the methadone clinics participating in this
Subcutaneous or intramuscular injection of BTH is the primary risk factor
for shooter's botulism. In addition to counseling IDUs to stop using BTH or,
at least, to minimize the amount of BTH that is injected, additional efforts
are needed to increase awareness of WB among IDUs and health care workers
who serve them and to increase access of heroin users to methadone detoxification
and maintenance programs. Physicians in the western United States should be
alerted to the potential for WB occuring among IDUs.