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Pain Associated With Injection of Botulinum A Exotoxin Reconstituted Using Isotonic Sodium Chloride With and Without Preservative
A Double-blind, Randomized Controlled Trial
Murad Alam, MD;
Jeffrey S. Dover, MD, FRCPC;
Kenneth A. Arndt, MD
Arch Dermatol. 2002;138:510-514.
ABSTRACT
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Context Botulinum A exotoxin is used for various indications, including the
treatment of dynamic forehead lines.
Objective To determine whether injection with botulinum A exotoxin reconstituted
with preservative-containing normal saline (isotonic sodium chloride) is less
painful than injection with exotoxin that has been reconstituted with preservative-free
saline.
Design Two arms: (1) retrospective study; (2) double-blind, randomized controlled
trial.
Setting A multiple-physician dermatology practice.
Patients (1) Retrospective study—20 consecutive adult patients presenting
for treatment of upper-face dynamic lines; (2) prospective study—15
consecutive adult patients presenting for treatment of upper-face dynamic
lines.
Intervention In prospective study only, one side (left or right) of the face was
treated with exotoxin reconstituted with preservative-containing saline, and
the other side, with exotoxin reconstituted with preservative-free saline.
Main Outcome Measures (1) Retrospective study—discomfort at current treatment (with
preservative-containing saline) compared with discomfort with most recent
prior treatment (with preservative-free saline); (2) prospective study—discomfort
on the side treated with preservative-containing saline compared with discomfort
on the side treated with preservative-free saline.
Results (1) Retrospective study—18 (90%) of 20 patients reported that
treatment with exotoxin reconstituted with preserved saline was less painful
than prior treatment with exotoxin reconstituted with preservative-free saline;
(2) prospective study—15 (100%) of 15 patients reported less pain in
the side of their face treated with exotoxin reconstituted with preservative-containing
saline (P<.001). Pain on the preservative-containing
side was 54% less. No difference in treatment efficacy between the sides was
observed by investigators or patients.
Conclusion Use of preservative-containing saline to reconstitute botulinum A exotoxin
can significantly decrease patient discomfort on injection.
INTRODUCTION
CONTRARY TO earlier practice beliefs, recent experience indicates that
the stability of botulinum A exotoxin is not impaired by reconstitution using
preservative-containing isotonic sodium chloride (saline).1-3
Additionally, the ability to store a vial of botulinum toxin over a period
of weeks rather than being forced to use the entire quantity in a single day
minimizes waste and has consequent economic advantages. Anecdotal reports
from patients and a few physicians have suggested that injections with botulinum
toxin reconstituted with preserved saline may also be less painful for patients.
The purpose of this study was to compare the pain associated with injections
of botulinum A exotoxin reconstituted using saline with and without preservative.
PATIENTS, MATERIALS, AND METHODS
The study had 2 arms, a retrospective analysis (RA) and a double-blind,
randomized controlled trial (RCT). For the RA, 20 consecutive adult patients
presenting to a multiphysician suburban dermatology practice for botulinum
A exotoxin treatment of upper-face dynamic lines were invited to participate.
For the RCT, 15 consecutive adult patients presenting to the same practice
for the same treatment were invited to participate. The RCT patients were
told that it had become possible to deliver injections in a manner that some
found less painful. It was explained that with their permission, 2 different
types of saline would be used, one on each side of the face. If they noted
a difference in discomfort, they would be offered whatever formulation they
found more comfortable at subsequent visits.
Informed consent was obtained from all patients. None of the consecutively
recruited subjects declined to participate. All the enrolled subjects were
in good general health.
MATERIALS
Our preservative-free saline was a 0.9% sodium chloride injection (American
Regent Laboratories Inc, Shirley, NY). Each milliliter contained 9 mg of sodium
chloride and sufficient water for injection. The pH range was 4.5 to 7.0,
adjusted with hydrochloric acid and/or sodium hydroxide when necessary. The
solution was supplied in 10-mL, single-dose vials and was pregnancy category
C.
Our preservative-containing saline was a bacteriostatic 0.9% sodium
chloride injection (Abbott Laboratories, North Chicago, Ill). Each milliliter
contained 9 mg of sodium chloride and 9 mg of benzyl alcohol added as a bacteriostatic
preservative. The pH range was 4.5 to 7.0. The saline might also have contained
hydrochloric acid for pH adjustment and was pregnancy category C.
Reconstitution of all vials of botulinum A exotoxin (Allergan Inc, Irvine,
Calif) with preservative-free and preservative-containing saline, respectively,
was performed by the same investigator (M.A.). There were no differences in
technique for the 2 types of saline. For dilution of each vial of botulinum
toxin, a fresh vial of diluent with intact flip-off cover was used. The final
dilution was 100 U of botulinum toxin per 5 mL of saline. Injections were
delivered from 1-mL tuberculin syringes with  -inch 30-gauge needles
(syringe, SlipTip; needle, PrecisionGlide No. 305106; both supplied by Becton
Dickinson and Company, Franklin Lakes, NJ).
EXPERIMENTAL DESIGN
The RA was performed to determine whether patients previously injected
with preservative-free toxin found the preservative-containing type less painful
on subsequent injection. Patients were asked to estimate, on a percentage
scale, how much more or less painful the preservative-containing injections
were than those from previous treatments without preservative (ie, X percent
more painful than pain associated with preservative-free, or Y percent less
painful than pain associated with preservative-free).
The RCT was then initiated (Table
1 and Table 2), with
patients randomly assigned to receive toxin reconstituted with preserved saline
to one side of the face (left or right) and toxin reconstituted with preservative-free
saline to the other side. Injections were for dynamic lines of the upper face.
Patients received treatment for glabellar, forehead, and/or lateral orbital
creases. Injection of one side of the face was completed before injections
on the other side were begun. For every second patient, the first set of injections
was with preservative-free botulinum toxin. Immediately after treatment completion,
patients were asked if injections on both sides had been equally uncomfortable,
or if one side had been more or less painful than the other. If one side had
been more painful, they were asked to estimate the pain on the preservative-containing
side as a percentage of that on the preservative-free side (eg, assuming the
right side was preservative-free: "How much more or less painful, in percentage
terms, were the injections on the left side than those on the right side?").
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Table 1. Patient Assessment of Discomfort Associated With Current Preservative-Containing
Botulinum Toxin Injection Treatment Compared With Immediately Previous Preservative-Free
Treatment*
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Table 2. Patient Assessment of Discomfort Associated With Right/Left
Split-Face Botulinum Toxin Injection Treatment With Preservative-Containing
and Preservative-Free Solution
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BLINDING TECHNIQUE
For the RCT, 1 investigator (M.A.) prepared preservative-containing
and preservative-free botulinum toxin in a sequestered space. For each patient,
both types were drawn up in identical syringes with identical needles and
hubs. There were no distinguishing marks. All injections were performed by
another investigator (J.S.D.), who was serially handed syringes by the preparer
(M.A.) and instructed on which side to begin injecting. Record keeping by
the preparer was done several feet behind the back of the injector. After
treatment, the injector asked the patient to estimate relative discomfort;
this eliminated the risk that a query by the preparer, who knew which side
was treated with preservative-containing solution, could bias the response.
RESULTS
In the RA arm of the study, 20 patients (18 women, 2 men) with a mean
age of 49 years (range, 30-61 years) were enrolled. Of these, 18 (90%) noted
that the botulinum toxin injections that they had just received (reconstituted
with preserved saline) had been less painful than their most recent previous
treatments (reconstituted with preservative-free saline). Except for 1 patient
treated for axillary hyperhidrosis, all of the patients' current and prior
treatments were for dynamic creases of the upper face. The patients who noticed
decreased pain with the current treatments estimated, on average, that these
treatments were 55% (range, 20%-80%) less painful than those in the past.
The 2 remaining patients, to the best of their recollections, recalled no
significant difference in pain between the successive treatments.
In the RCT arm of the study, 15 women with mean age of 48 years (range,
33-64 years) were enrolled. Of these, 15 (100%) reported that they experienced
less pain in the side of the face treated with preservative-containing botulinum
toxin injections than in the side treated with preservative-free toxin. Statistical
analysis was performed by application of the binomial probability distribution.
The results were determined to be highly statistically significant (P<.001) despite the small sample size.
The average pain level on the preservative-containing side was 54% less
severe than on the preservative-free side (range, 33%-80%). Subjective pain
assessments of the preservative-free solution communicated a greater degree
of "piercing," "stinging," "sharpness," and "pinching," whereas the preservative-containing
side "barely hurt" or "didn't hurt at all."
COMMENT
The manufacturer of botulinum A exotoxin (Allergan Inc) has historically
encouraged reconstitution of the desiccated form with unpreserved saline.
This formulation was experimentally shown to be efficacious and stable in
initial clinical trials. While alternative types of saline have not been reported
to be any less effective, Allergan officially continues to recommend dilution
with preservative-free saline. Technical support personnel at Allergan also
assert that use of preservative-free saline may result in less painful injections
(personal telephone communication, Botox physician help line, Allergan Inc,
May 13, 2001).4 Roger Aoki, MD, a researcher
at Allergan, has found that botulinum A exotoxin reconstituted with preserved
saline is stable with refrigeration for 5 weeks (personal communication, 2000).
Others have also found that dilution with preserved saline seems to leave
intact the efficacy of botulinum toxin.5 While
few physicians store reconstituted toxin for more than a few days, the ability
to do so for limited intervals conserves material, reduces physician and patient
costs, and permits more convenient scheduling for patients. Refrigeration
of botulinum toxin reconstituted with preserved saline has enabled use of
a given vial over a period of several days to weeks.
This study demonstrates that patient comfort is also enhanced by botulinum
toxin hydrated with preserved saline (Table
1 and Table 2). Both
the RA and the RCT showed a statistically significant lower level of injection
pain associated with the use of preserved saline. More importantly, the difference
was clinically significant. Patients noticed a dramatic reduction in unpleasant
sensation, which they quantified as an approximately 50% diminution. The estimates
of pain reduction were strikingly similar for both the RA and RCT comparisons.
No patient preferred the botulinum toxin diluted with preservative-free saline.
Interestingly, most patients described the initial punctures with the
preservative-free syringes as feeling sharper, as if with a different needle,
even though exactly the same hardware was used to deliver both types of injections.
Patients also reported increased pain and pressure associated with preservative-free
toxin once the needle was in and the plunger was depressed. The 1 patient
who received treatment for axillary hyperhidrosis encountered the same sensations.
The results do not seem unique to injection of the upper face.
Follow-up self-report indicated that none of the treated patients in
either arm of the study noticed any difference in efficacy between the preservative-containing
and preservative-free injections. Similarly, in all instances in which left-right
treated patients were seen in the clinic for other reasons within 4 months
of the injection protocol, the treating physicians observed no differences
between the 2 sides either at rest or with voluntary contraction.
Investigations were performed to confirm that the pain-muting effects
of bacteriostatic saline observed in this study were not due to differences
in pH between the bacteriostatic and preservative-free saline. Manufacturers
of both the diluents used were contacted and queried as to the typical pH
of their products. The pH range was reported to be 4.5 to 7.0 for the preservative-containing
as well as the preservative-free saline made by each company. Additionally,
Abbott Laboratories noted that their bacteriostatic saline had a usual tested
pH of 5.0, and their preservative-free saline, 5.6 (personal communication,
Abbott Laboratories, Pharmacy, Hospital Division, May 14, 2001). Computations
by American Regent Laboratories revealed a mean tested pH of 5.33 for all
batches of 10-mL preservative-free saline vials produced at their facility
from 1999 through May 2001 (personal communication, American Regent Laboratories
technical support, May 14, 2001). Apparently, preservative-free and preservative-containing
saline do not differ significantly in terms of pH. Slightly greater acidity
is the norm for preservative-containing saline, and while relative acidity
suggests more pain on injection, such an outcome was not observed.
The remaining major difference between the 2 categories of saline we
studied was the presence or absence of benzyl alcohol. There is substantial
evidence that benzyl alcohol has anesthetic properties. At least 4 double-blind,
randomized controlled trials have been conducted to compare in the same individuals
the pain experienced on subcutaneous injection of otherwise identical solutions
using preservative-free normal saline and benzyl alcohol–containing
normal saline.6-9
In one such study,7 preservative-free and preservative-containing
saline were injected without combination with other agents to facilitate anesthesia
before intravenous catheter placement. Five other substances, including 1%
lidocaine, 1% lidocaine with preservative, and alkalinized 1% lidocaine with
preservative, were also examined in similar fashion. Of the 7 injectants,
benzyl alcohol in normal saline was associated with the lowest mean ±
SD pain scores (0.61 ± 0.11, on a 10-cm visual analog pain scale),
and normal saline, with the highest scores (3.97 ± 0.18). The difference
was statistically significant.
In a similar study,9 20 healthy volunteers
were injected with each of 6 solutions, among which were normal saline, preserved
normal saline, 0.2% lidocaine in normal saline without preservative, and 0.2%
lidocaine in preserved saline. Degree of anesthesia was assessed by pinprick
every minute for 20 minutes. Normal saline alone caused the most pain, and
both preservative-containing saline and lidocaine with preservative-containing
saline caused the least pain. Adequate anesthesia was obtained for 4 minutes
with preservative-containing saline alone. In the dermatology literature,
Williams and Howe8 graded the pain induced
by intradermal and subcutaneous injections of 1% lidocaine diluted with preservative-free
and benzyl alcohol–containing saline. On average, the 20 subjects found
the preservative-containing lidocaine 27% less painful on injection. Duration
of anesthesia was 29% longer with the preservative-containing solution.
The anesthetic action of benzyl alcohol has also been investigated by
physicians trying to minimize the pain of subcutaneous injection with recombinant
human erythropoietin (epoetin alfa) in patients with renal disease.10 Twenty-eight hemodialysis patients received epoetin
injections diluted with saline with and without benzyl alcohol. Results showed
a statistically significant difference in pain perception at times 0, 10,
and 15 minutes on both a visual analog scale and a verbal descriptive pain
scale. Preservative-containing solutions were less painful in all instances.
Patient differences were also noted, with several patients reporting no pain
with the unpreserved saline.
Numerous other studies with less symmetric design have corroborated
the anesthetic properties of benzyl alcohol.10-16
For pain relief during intravenous line placement, intradermal preserved saline
alone has been shown to be as effective as intradermal 1% lidocaine hydrochloride.10 Intradermal injections of preservative-containing
saline with 1:100 000 epinephrine have been found to be 48% less painful
than injections of unpreserved saline alone (P =
.008).11 Cutaneous anesthesia in patients allergic
to lidocaine may be better achieved with injection of preserved saline with
epinephrine than with injection of 1% diphenhydramine.12
The former was statistically significantly less painful on injection (5 mm
vs 55 mm median pain score on 100-mm visual analog pain scale) and provided
equally long-lasting anesthesia.
For eyelid surgery, 2% lidocaine with 1:100 000 epinephrine diluted
1:9 with 0.9% bacteriostatic saline caused less discomfort on injection than
both plain 2% lidocaine with 1:100 000 epinephrine and 2% lidocaine with
1:100 000 epinephrine buffered 1:9 with 8.4% sodium bicarbonate.15 According to patient reports, the level of anesthesia
induced following injection did not differ for the various solutions. Benzyl
alcohol–containing saline also seems to be a useful anesthetic in children.
In a randomized convenience sample of 99 children older than 6.8 years seen
in an emergency room, saline with benzyl alcohol and 1% lidocaine were equally
effective as intradermal anesthetics for intravenous line placement.16
Indeed, normal saline with benzyl alcohol has all the qualities of an
ideal anesthetic agent.17 Pain on application
and pain on venipuncture are both low, as is cost, and the substance is convenient
to use. Lidocaine may provide longer and better anesthesia, but its pain on
application is greater.
Benzyl alcohol–containing saline should not be injected intrathecally18-19 and has been associated with toxic
effects in newborns.20 Obviously, neither of
these caveats would preclude its use in reconstituting botulinum toxin for
intramuscular or intradermal injection in adults.
In summary, this study indicates that reconstitution of botulinum toxin
with preservative-containing saline can markedly decrease patient discomfort
at the time of injection. The difference is statistically and clinically significant.
Given the increasing evidence, confirmed in our investigation, that preservative-containing
and preservative-free botulinum toxin preparations are equally safe and effective,
physicians who do not do so at present should consider using the preservative-containing
solution. Indeed, since the completion of this study, we have discontinued
use of preservative-free saline to dilute botulinum toxin in our practice
and have noticed a sustained increase in patient satisfaction associated with
the change. Minimizing patient pain is an important physician responsibility.
Elective procedures such as injections for dynamic creases should be particularly
devoid of unnecessary suffering.
AUTHOR INFORMATION
Accepted for publication August 29, 2001.
This study was supported in part by clinical practice funds from SkinCare
Physicians, Chestnut Hill, Mass.
Corresponding author and reprints: Murad Alam, MD, 7515 Main St,
Suite 240, Houston, TX 77030 (e-mail: murad{at}alam.com).
From SkinCare Physicians, Chestnut Hill (Drs Alam, Dover, and Arndt),
and Harvard Medical School, Boston (Dr Arndt), Mass; and Dartmouth Medical
School, Hanover, NH (Drs Dover and Arndt).
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