S McLean R Bruno submission document

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Harm reduction by filtration
National Drug Strategy Consultation
MDP 27
GPO Box 9848
Canberra ACT 2601
Submission to National Drug Strategy
Harm reduction by syringe filters: A cost-effective means
of improving the health of injecting drug users
Professor Stuart McLean and Dr Raimondo Bruno
5 February 2010
SUMMARY
Injecting drug users (IDUs) are liable to suffer harm not only from the
illicit drugs themselves, but also from inadvertent injection of unwanted
material present in these illicit drugs. This additional material includes
insoluble particles and infectious microorganisms, and these are
responsible for much of the medical complications associated with
injecting illicit drugs: skin and soft tissue infections, endocarditis
(infection of heart valves), pulmonary (lung) complications, and impaired
blood flow to the limbs, leading to necrosis (tissue death) and
amputation.
The needle and syringe program (NSP) was introduced in Australia in the
1980s to counter the HIV epidemic, and it has been highly cost-effective
in reducing viral infections by HIV and hepatitis C1. Filters are able to
remove microorganisms and other particles but they are not uniformly
available through NSP sites, and may not be used if available because of
problems with the filters blocking and a belief amongst IDUs that some of
the drug is lost on the filter. Despite these concerns and limited
availability, one-third of frequent IDU in mainland jurisdictions have
recently used syringe filters 2, and this rate is significantly greater in
Tasmania (45%) where access to filters is subsidised 3. However, one-fifth
of IDUs do not use any filters and a further two-fifths use cigarette
filters, which are ineffective as they only remove the largest particles 4 5.
The problem of particles is particularly severe when IDUs prepare
injections from tablets that are designed for oral administration. The
tablets are crushed and mixed with water and the mixture is injected.
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Harm reduction by filtration
However, tablets contain a large proportion of inactive ingredients to
facilitate the manufacture, storage and therapeutic effect of the drug.
Many of these ingredients are not water soluble and their injection can
cause complications. The long-acting formulations of morphine sulfate,
such as MS Contin®, are commonly used this way. These tablets contain
a wax matrix which is used to confer the prolonged effect of morphine. A
major problem is that the wax produces a large amount of insoluble
particulate material when the tablet is crushed for injection. The
prevalence of injection of morphine and other pharmaceutical opiates
has increased in recent years, and has been noted as an issue of concern
by the Royal Australian College of Physicians [see:
http://www.racp.edu.au/index.cfm?objectid=EA87198D-CA47-AB21072D9B2F26FD4AA3]
We have studied the particle content of injections prepared from longacting morphine tablets (MS Contin®) 5. Each unfiltered injection
contained tens of millions of particles which ranged in size from smaller
than 5 m to greater than 400 m. Intravenous injection of these
particles is harmful, as they will lodge as emboli in the blood vessels,
leading to tissue death. We found that virtually all of the particles can be
removed by appropriate filtration, and that effectively the full dose of the
drug can be retained by good preparation practices.
It is our recommendation that effective filters and instructions on their
use should be uniformly provided at NSP outlets. Appropriate syringe
filters are able to remove particles and, using the 0.2 m pore size, can
also remove microorganisms (bacteria and fungi, although not viruses).
Thus with a single additional step, much of the harm caused by
injections prepared from pharmaceutical tablets can be eliminated. The
use of effective filters would also be expected to reduce the harm caused
by injection of illicit drugs other than morphine from tablets, at least so
far as this is due to the presence of insoluble particles and non-viral
microorganisms.
A full cost-benefit evaluation of this intervention has not yet been done.
However, since the filters would be supplied through existing NSP outlets
the costs of implementation would be not much more than the wholesale
price of the filters ($1-2 each). The most common causes of hospital
admissions of IDUs, soft-tissue infections and lung complications, can be
prevented by effective skin-swabbing and filtration of injections, saving
the cost of hospitalization which is $A3,907 per average of all hospital
admissions 6. Some idea of the national cost comes from the estimated
cost to the public health system of treating injection-related injuries and
diseases (excluding HIV and other viral infections) for Victoria, NSW and
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Harm reduction by filtration
Queensland, which was $19 million in 2005/6 7. Usually IDUs only seek
treatment for the most serious reactions, and these are greatly
outnumbered by potentially serious and non-serious reactions7.
Therefore these known health costs represent only a small fraction of the
total health impact of injecting drug use.
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Harm reduction by filtration
BACKGROUND
Harm due to non-drug contaminants of injections
Injecting drug users (IDUs) are liable to suffer harm due to the adverse
effects of the drugs, such as respiratory failure after overdose with
opiates or psychotic episodes after heavy use of amphetamines 8.
However, in addition to these drug-related harms, a great number of
medical complications can be attributed to, or are aggravated by,
contaminants and other extraneous material in the injections 9-12. Some
of these contaminants are deliberately added to illicit drug preparations
as diluents (eg quinine, lactose, caffeine, sucrose) and some occur during
production (eg chemical byproducts, dirt) 13. In the case of
pharmaceutical tablets, various inactive substances are added during
production to facilitate the manufacture, stability and therapeutic
effectiveness of the tablet 14. The additives, or excipients, include a
number of substances which are not soluble in water: talc, cornstarch,
cellulose, magnesium stearate, waxes. Whatever their source, the
injection of insoluble particles can cause health complications.
Effects of injection of particles
There are two broad types of problem which arise from the injection of
particles. Particles tend to be irritant to tissue (think of dust in the eye),
and can cause inflammation at the site of injection. Damage to the vein
can lead to inflammation (phlebitis), formation of a clot (thrombus) or
both (thrombophlebitis). This can block the flow of blood leading to a lack
of oxygen in the downstream tissue (ischaemia). This condition can occur
near the site of injection or in a deep vein (deep venous thrombosis or
DVT) and is considered to be common amongst IDUs although often
untreated12. Sometimes the injection is made into the skin or muscle,
either because it misses the vein, or because the vein has been too
damaged from previous injections 10 13. The inflammation in these tissues
leads to a lump (granuloma) involving accumulation of white blood cells
and deposition of scar tissue. This can progress, for example it it
becomes infected, leading to an abscess, and chronic skin ulcer 15.
The second type of problem occurs when a particle is injected into the
bloodstream where it moves downstream until it encounters a vessel too
small to pass, where it lodges forming a blockage, or embolism. This
results in a lack of blood flow to the downstream tissue (ischaemia)
which can lead to death of this tissue (necrosis) 9 16. When injected into a
vein in the arm or leg, particles will be carried through ever-larger vessels
to the heart, and then to the pulmonary circulation where they will
encounter progressively smaller vessels from arteries to arterioles to
capillaries 17. Particles larger than capillaries (about 7-9 m, where one
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Harm reduction by filtration
m or micrometer is one thousandth of a millimetre) will block there,
while larger particles will block the arterioles (9-40 m diameter) or small
arteries (300-400 m diameter). Particles larger than this are unlikely to
be taken up through the syringe needle and will not be injected.
Sometimes the injection is made into an artery in the arm or leg, either
accidentally or deliberately when the veins have become too damaged to
access. In this case the embolism and consequent ischaemic damage
occurs in the limb and can lead to amputation of digits or the limb itself,
depending on the site of the blockage 13 18.
Microorganisms, such as bacteria and fungi, are also particles and can
be removed by filtration provided the pore size is small enough 19. A filter
size of 0.2 m is regarded as sterilizing since it will remove these
microorganisms, although it will not remove viruses. Fortunately, the
viruses of most concern for IDUs (HIV and hepatitis C) are blood borne
and can be avoided by not sharing injection equipment 10.
Medical complications of injecting drug use
In some cases the drug itself can produce critical illness, for example
stroke and myocardial infarction after cocaine injection 8. Many
substances have been used to dilute illicit drugs, including quinine,
lactose, caffeine, sucrose 13. Although it is water-soluble, quinine is
capable of damaging the walls of blood vessels and its injection can
cause clotting (thrombosis) in veins 15.
However, there are a large number of medical complications of injecting
drug use which are attributable, wholly or in part, to particles and
microorganisms present in the injection and which could be removed by
filtration. The most common complications requiring treatment which are
experienced by IDUs are skin and soft tissue infections, and diseases of
the heart and lungs (Table 1). These sites have the greatest contact with
the injection constituents, either as sites of injection (skin, muscle), or as
the first organ of contact in the circulation (heart), or as having the first
microcirculation of contact (in the lungs).
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Harm reduction by filtration
Table 1. Selected1 Medical Complications of Injecting Drug Use
Tissue
Injection into vein
Skin and muscle
Cellulitis
Abscesses
Nodules
Complication2
Blood vessels and lymphatics
Thrombophlebetis
Thrombosis
Pseudoaneurysm
Necrosis
Necrotizing ulcers
Necrotizing fasciitis
Chronic venous insufficiency
Lymphoedema
Heart
Endocarditis
Lungs
Fibrosis
Granuloma
Nodules
Conglomerate masses
Pulmonary hypertension
Panacinar emphysema
Septic arthritis
Osteomyelitis
Skeleton
Injection into artery
Limbs
Ischaemia
Necrosis
Gangrene
Amputation
Infections
Local and systemic infections with Staphylococci, Streptococci,
Psudomonas, Clostridium.
1A
very large number of complications have been reported, involving
almost any body organ 20
2All of these complications have been associated with injection of
particles
References: 9-11 13 16 21 22
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Harm reduction by filtration
The initial damage may lead to local tissue necrosis which enables
pathogenic microorganisms to colonise the tissue, and the resulting
infection leads to more serious disease. For example, in the skin,
irritation causes a type of inflammation (cellulitis), then a lump of scar
tissue (granuloma). The damage can progress to local infection (skin
abscess) and, if this should spread to the bloodstream, a serious
systemic infection.
The microoganisms usually involved are bacteria which are commonly
found on the skin (Staphylococcus aureus and Streptococcus species), and
infections are associated with a failure to disinfect the injection site 13 15
23, indicating that the IDU has probably become infected by omitting to
sterilize their skin 10 15. In the heart, it is the tricuspid valve which has
been most commonly infected in IDU-related endocarditis 11 24. The
tricuspid is the valve through which the injection constituents pass on
the way to the lungs. Here, the major pathogens are Staphylococci,
Pseudomonas and the fungus, Candida, all of which are commonly
present in the environment 10.
The lungs are the primary target organ in which small vessels are
blocked following the intravenous injection of particles. This has been
well described for talc, which produces characteristic lesions in the lungs
9 16. With repeated injections the talc accumulates in the lungs. The talc
can migrate out of the blood vessels into the lung tissue where an
inflammatory reaction leads to the development of scar tissue (fibrosis)
which takes the form of small lumps or nodules. These nodules can
coalesce into larger conglomerate masses. The overall picture is one of
progressive damage involving the lung and other chest structures leading
to a reduction in lung efficiency (emphysema) and impaired breathing
(dyspnoea) and sometimes elevated blood pressure (pulmonary
hypertension). The latter carries a high risk of heart failure.
Evidence that particles cause complications
The most direct evidence that particles cause complications comes from
studies of IDUs who used crushed tablets. Talc and other insoluble tablet
fillers have been implicated in lung and other thoracic complications 9 16
25-27. The talc deposits could be seen in histological specimens from the
lung. Injection of crushed buprenorphine tablets causes many skin
conditions: cellulitis, abscess, nodules, necrosis, thrombophlebitis and
oedema 13. Crospovidine, an insoluble polymer used in pharmaceutical
tablets, has been found as particles in the pulmonary arteries and
extravascular foreign body granulomas in the lungs of injecting drug
users 28. Deep neck abscesses have been found in injecting Ritalin® users
29. This was related to an inflammatory foreign body reaction to the
inactive components in the tablet, followed by superinfection with oral or
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Harm reduction by filtration
skin flora. Injection of buprenorphine tablets has been assocated with
puffy hand due to obstruction of the lymph ducts 30. Injection of
buprenorphine tablets has also been associated with infective
endocarditis and Staph. aureus septicaemia with a high mortality rate of
42% 22.
Other illicit drug preparations contain insoluble particles, although the
composition of these is not well understood. However, the characteristic
track marks seen in regular IDUs are due to the deposition of particles
under the skin 10. It is also generally considered among experts that
contaminating particles are a major contributing factor to physical
complications of drug abuse, especially when microbes are considered 911 13 15 16.
Finally, it is biologically plausible that insoluble particles are major
contributors to health complications. Unlike insoluble particles, drugs
and other substances which are in solution are not usually able to cause
blockages in blood vessels or deposit in tissues. Also, despite the
exceptions of quinine, and cocaine (which can excessively constrict blood
vessels), drugs and inert diluents in solution do not usually cause
damage to blood vessels, unlike particles which can physically damage
the vessel walls leading to thrombosis or even laceration and ballooning
of the wall (pseudoaneurysm) 9.
The infection which commonly follows tissue damage is due to non-viral
micoorganisms, bacteri and fungi, which are also particles. These
infections may be a primary cause of complications 9 13. Infections which
commence locally (eg in the skin or a heart valve) can progress to involve
the entire body 10 15.
Evidence that many infections are due to poor injection technique
It is self-evident that exclusion of microorganisms will prevent infection,
and this underlies the use of sterile injection procedures in normal
medical practice. Several authors have commented that IDU infections
are attributable to non-sterile injection procedures 9 10 13 31 32. Vlahaov 23
showed that skin cleaning lowered the incidence of abscesses and
endocarditis. Caflisch 19 found that filtration through a sterilizing 0.22
m filter, but not a 20 m filter or cigarette filter, was very effective in
removing bacteria from illicit drug injections. In a large Australian study,
Dwyer and colleagues 7 12 found that not washing hands was associated
with an increased risk of infections amongst IDUs. They recommended
hygienic injecting procedures and filtration as important protective
measures.
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Harm reduction by filtration
Recent studies show that, despite this evidence, while the majority of
IDUs (84%) do clean their injection site prior to injection12, only 14%
always wash their hands7 and only 31% have used a filter in the past 12
months2 33.
Injections directly into the skin or muscle, which is done when the veins
have become too damaged, is another strong risk factor for abscesses 15.
Procedures used by IDUs
We have surveyed 260 IDUs in the Hobart area to determine the filtering
methods they applied on their last occasion of morphine injection 5. This
was selected as it was the most common opiate drug injected in
Tasmania3, and preparations or morphine have very high levels of
particulate contamination. Despite this, the survey revealed that, on
their last occasion of morphine injection, one third used no filter, 41%
used cigarette filters and 21% used syringe filters5. Smaller numbers
used other makeshift filters (cotton balls, tampons, etc) or combinations
of filters.
BENEFITS OF FILTRATION OF INJECTIONS
Particles can be removed by filtration
We have recently characterised the particles present in injections
prepared from extractions of crushed morphine tablets (MS Contin®), and
shown that they can be removed by appropriate filtration 5. The tablets
were crushed and mixed with water and filtered using methods based on
those employed by IDUs.
Appearance of injection mixtures
The unfiltered extracts were milky in appearance and had clearly-visible
white insoluble material (Figure 1, tube 1). The extract was then passed
through various filters used by IDUs. The commonly-used cigarette filter
only removed some of the larger particles, and the filtrate had the
appearance of diluted milk (Figure 1, tube 2). The small-pore syringe
filters (0.45 m and 0.22 m) blocked with the unfiltered injection, but if
the unfiltered solution was first passed through a cigarette filter and
then the syringe filter, this passed through easily, giving a solution that
was clear and bright (Figure 1, tube 3).
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Harm reduction by filtration
Figure 1. Injections prepared from a tablet of morphine (MS Contin®)
crushed and mixed with 3 mL water. 1 = unfiltered; 2 = cigarette filtrate;
3 = 0.22 m syringe filtrate.
The injection mixtures were then examined under a microscope. The
unfiltered extract showed many particles ranging in size from less than 5
m to more than 400 m (Figure 2A). After passage through a cigarette
filter there were still a large number of particles, although some of the
larger particles had been removed (Figure 2B). When this filtrate was
passed through a syringe filter (0.22 or 0.45 m), nearly all of the
particles were removed. A small number of particles remained, due to the
inevitable environmental contamination (eg by dust) of a working area
which is neither sterile nor particle-free, as is used by IDUs.
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Harm reduction by filtration
Figure 2A.
Photomicrograph of a
sample of the unfiltered
injection. Note that there
are many particles, with a
large range of sizes and
that their shapes are
highly irregular.
Figure 2B.
Photomicrograph of a
sample of the injection
after passage through a
cigarette filter. Note that
there are still many
particles, although fewer
of the largest particles.
Figure 2C.
Photomicrograph of a
sample of the injection
after passage through a
syringe filter (0.45 m).
Note that nearly all of the
particles have been
removed by filtration. The
remaining particles are
most likely due to normal
environmental
contamination.
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Harm reduction by filtration
Particle counts per injection
The number of particles in each size group was counted in a small
sample of each mixture, and used to estimate the number of particles in
each injection. The unfiltered injection mixture was densely packed with
tens of millions of particles, especially in the range 5 – 50 m (Figure 3,
Unfiltered). Although not apparent in Figure 3, there were significant
numbers of particles in the largest size group (larger than 400 m) – on
average, 12,000 per injection of a single tablet.
Although the cigarette filter removed some of the larger particles (larger
than 50 m) a large number of particles of all sizes remained (Figure 3,
Cigarette Filter). Small-pore syringe filters (0.45 m and 0.22 m) were
not very satisfactory with the unfiltered injection, as they tended to
block. However, syringe filters were very effective once the solution had
first been passed through a cigarette filter: this passed through the
syringe filter easily and yielded a solution that was essentially particlefree (Figure 3, 0.22 m Filter). The blockage of these otherwise extremely
effective syringe filters without this pre-filtering step is cited by many
consumers as one reason that they do not routinely use these devices.
The finding that the problem of blocked filters was removed by a simple
pre-filtering step is a good example of the importance of the requirement
for educating IDU about the most effective use of these filters, rather
than solely providing the equipment.
Particles in Injections
0
3000
2000
1000
0
Particle size (m)
Particle size (m)
5000
4000
3000
2000
1000
0
>4
0
10 0 
040
0

50
-9
9

20
-4
9.
9

10
-1
9.
9

59.
9

1000
4000
Particles per injection
(thousands)
2000
(7112)
5000
>4
0
10 0 
040
0

50
-9
9

20
-4
9.
9

10
-1
9.
9

59.
9

3000
0.22 m Filter
Cigarette Filter
Particles per injection
(thousands)
4000
>4
0
10 0 
040
0

50
-9
9

20
-4
9.
9

10
-1
9.
9

59.
9

Particles per injection
(thousands)
Unfiltered
5000
Particle size (m)
Figure 3. Numbers of particles by size in morphine tablet injections. The
unfiltered injection mixture was first filtered through a cigarette filter,
then through a 0.22 m porosity syringe filter. The numbers are
expressed in thousands (that is, 5,000 units = 5 million particles) with
mean and SD of 3 replicates.
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Harm reduction by filtration
Recovery of morphine after filtration
One reason IDUs do not filter their injections is a belief that some of the
dose will be lost in the process. We found that this need not be the case,
since by rinsing the filters, the morphine could be recovered without
significant loss (Figure 4). ). This is consistent with findings by another
research group at the University of Otago 34.
Morphine Recovery
Morphine recovered
(mg)
60
50
40
30
20
10
m

er
Fi
lte
r
0.
22
ig
.F
ilt
C
U
nf
ilt
er
ed
0
Figure 4. Amount of morphine recovered before and after filtration of a
60 mg tablet (mean  SD, N = 3). Note that an individual tablet may
legally contain between 55 and 65 mg of morphine.
Conclusions
Our study has shown that the MS Contin® crushed-tablet mixture
injected by many IDUs across Australia contain tens of millions of
particles in each injection. Such particles, together with microorganisms,
are known to be the underlying cause of much of the harm associated
with this practice. However, appropriate filtration can remove virtually all
of the particles including microorganisms, and would consequently be
expected to greatly reduce the harm caused by injecting mixtures from
crushed tablets. We have since examined injection mixtures prepared
from another pharmaceutical, Oxycontin®, with similar results. By
extension, the particle-related harm from injection of other illicit drug
preparations could also be reduced by effective filtration methods.
Cautions
Although what we already know justifies the immediate use of filters to
reduce injection-related harm, more studies are required to improve the
evidence-base for this practice. There are a large number of filters
available, made from different materials and with different porosities.
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Harm reduction by filtration
Sterilizing filters are designed to remove relatively few microorganisms
from an essentially clean solution, and the manufacturers caution
against their use for heavily contaminated suspensions. Even the coarser
filters (larger than 0.45 m) are liable to be damaged if overloaded with
particles or if high pressures are used. Thus, we need to investigate the
use of particular filters for different illict drug injections to thoroughly
evaluate the procedures. The effectiveness in removing microorganisms
(bacteria and fungi) should also be confirmed.
It is not possible to prepare an injection to pharmaceutical standard
without clean facilities, as particles and microorganisms from the
environment will contaminate the preparation. The injection of illicit
substances will remain inherently dangerous due to the effects of the
drugs themselves and filterable (soluble) contaminants. However, the
harm associated with unfiltered or ineffectively filtered injections can be
greatly reduced by effective filtration.
RECOMMENDATIONS
1. Filtration of all injections through 0.22 m filters, together with basic
aseptic technique (cleaning of hands, injection sites and equipment), has
the potential to dramatically reduce the harm associated with injection of
illicit drugs, both diverted pharmaceuticals and illicit drugs such as
heroin and methamphetamine.
2. The Needle and Syringe Program should be extended to include 0.22
m sterile syringe filters capable of filtering crushed tablet extracts in a
single operation. Filtration through a coarse then a ‘sterilizing’ filter is a
simple procedure which could dramatically reduce the harm associated
with injecting drug use. This could be done by connecting together two
filters of the required porosity, or with a combined two-stage sterile
0.8/0.22 m syringe filter, which are commercially available.
3. The equipment (needles, syringes, swabs, filters) should be available in
NSP outlets together with trained staff and educational material to
increase the uptake of safer injecting practices by IDUs.
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Harm reduction by filtration
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Harm reduction by filtration
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17
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