Abstract
Background: Intra-articular narcotics have proven efficacy for
providing pain relief following knee arthroscopy. This effect is short-lived.
Methadone, with its long serum half-life (thirty-five hours, compared with two
hours for morphine) could provide improved and prolonged pain relief. The
purpose of the present study was to examine the effects of an intra-articular
injection of methadone on postoperative analgesia following arthroscopic
anterior cruciate ligament reconstruction.
Methods: Sixty-five skeletally mature patients undergoing primary
anterior cruciate ligament reconstruction were randomly assigned to one of
three groups, all of which received an intra-articular injection consisting of
9.5 mL of 0.5% bupivacaine with 1:200,000 epinephrine at the completion of the
procedure. In addition, the remaining 0.5 mL of the syringe was filled with
one of three substances. The study group (twenty-five patients) received 5 mg
of methadone, the comparison group (twenty-one patients) received 5 mg of
morphine, and the control group (nineteen patients) received 0.5 mL of saline
solution. All supplemental pain medications were given on an as-needed basis,
recorded, and converted to morphine equivalents. Specific variables that were
measured included supplemental analgesia requirements during both the
inpatient period and the outpatient period (from the time of discharge to the
seventh postoperative day) and pain scores.
Results: There was no significant difference in inpatient (p =
0.998) or outpatient (p = 0.887) supplemental analgesic requirements or pain
scores between the methadone group (Group 1) and the control group (Group 3).
The morphine group (Group 2) required significantly less inpatient (p = 0.014)
and outpatient (p = 0.044) supplemental analgesia compared with the control
group (Group 3). There were no complications.
Conclusions: The present report represents the first known study of
the use of intra-articular methadone and establishes that this analgesic is
safe at a single dose of 5 mg. At this dose, however, methadone does not
provide improved postoperative analgesia following arthroscopic anterior
cruciate ligament reconstruction. In contrast, intra-articular morphine does
appear to be effective for decreasing postoperative pain.
Level of Evidence: Therapeutic Level I. See Instructions
to Authors for a complete description of levels of evidence.
Several authors have studied the use of intra-articular opioids for
pain relief following arthroscopic anterior cruciate ligament reconstruction.
Morphine, the most widely studied intra-articular narcotic, has demonstrated
efficacy for the relief of pain following arthroscopic knee surgery, including
anterior cruciate ligament
reconstruction1-3.
The serum half-life of morphine is approximately two hours, but when used
intra-articularly, the analgesic effects have been shown to last up to
twenty-four
hours1-3.
The dosage of intra-articular morphine that is used has varied widely in the
literature and in
practice4-6.
Methadone is a potent, long-lasting analgesic with high intrinsic activity
at the opioid receptors. Because of its high protein-binding activity and low
lipid solubility, its serum half-life is approximately thirty-five
hours7. When
methadone is administered intra-articularly, the analgesic effects may
possibly be extended well beyond twenty-four hours. This method of
administration could provide long-lasting pain relief with a decreased need
for supplemental analgesia. To our knowledge, there have been no studies on
the use of intra-articular methadone.
The purpose of the present study was to examine the effects of
intra-articular methadone on postoperative analgesia following arthroscopic
anterior cruciate ligament reconstruction as compared with the effects of both
a control (saline solution) and intra-articular morphine.
In order to establish the safety of intra-articular methadone, a canine
model was tested in a preliminary
study8. Nine
coonhound dogs were injected with a combination of methadone and bupivacaine
in one knee and with a combination of bupivacaine and saline solution in the
contralateral knee. Dogs were killed on the first, fourteenth, and
twenty-eighth days, and a veterinary pathologist examined the knees. There
were no immunological or histopathological changes in the synovial fluid,
synovial tissue, articular cartilage, menisci, or cruciate ligaments of any of
the necropsy specimens. There also were no significant serum levels of
methadone at six and twenty-four hours following injection. Following that
study, the Food and Drug Administration approved intra-articular methadone for
study in humans as an investigational new drug (IND #57,679).
The institutional review board approved the study, and all patients
provided informed consent. We conducted a prospective, randomized, controlled
trial. Between January 2001 and September 2003, all patients undergoing
primary anterior cruciate ligament reconstruction at our institution were
considered for enrollment. The inclusion criteria included (1) an age of
eighteen to sixty-five years, (2) class-I or II health status according to the
criteria of the American Society of Anesthesiologists
(ASA)9, (3) an
ability and willingness to undergo general anesthesia, (4) anterior cruciate
ligament reconstruction involving the use of hamstrings or bone-tendon-bone
autograft. The exclusion criteria included (1) a known allergy to any of the
study medications (bupivacaine, methadone, and morphine), (2) a history of
substance abuse, (3) a history of chronic pain, (4) current pregnancy or
lactation, (5) a requirement for an indwelling drain postoperatively, (6) use
of a monoamine oxidase inhibitor, (7) preoperative use of opioids or other
pain medications, (8) intraoperative inflation of a tourniquet, (9)
multiligamentous reconstruction (repair or reconstruction of the posterior
cruciate ligament, medial collateral ligament, or posterolateral corner of the
knee), and (10) revision anterior cruciate ligament reconstruction.
Operative Protocol
Preoperatively, all patients had achieved a full range of motion (equal to
that on the contralateral side). All subjects received a standardized general
anesthetic (see Appendix). A tourniquet was not used during any of the
procedures. Preoperatively, all patients were assigned, with use of a
random-numbers table, to receive a 10-mL intra-articular injection consisting
of one of three combinations of medications. Group 1 (the study group)
received 0.5% bupivacaine with 1:200,000 epinephrine (9.5 mL) and 5 mg of
methadone (0.5 mL), Group 2 (the morphine group) received 0.5% bupivacaine
with 1:200,000 epinephrine (9.5 mL) and 5 mg of morphine (0.5 mL), and Group 3
(the control group) received 0.5% bupivacaine with 1:200,000 epinephrine (9.5
mL) and 0.9% normal saline solution (0.5 mL). The randomization was performed
in the pharmacy department before the day of surgery. The medications were
prepared in the pharmacy on the day of surgery with use of aseptic technique
under a laminar flow hood. The sterile 10-mL syringe containing one of the
three combinations was emptied into the knee through the 3-mm outflow cannula
after suture closure of the remaining portals and any skin incisions. No
drains were used. The contents of the syringe were unknown to the surgeon, the
anesthesia provider, and the patient. A sealed master list that matched the
syringe number and its contents was maintained in the pharmacy in case of
emergency. There was never a need to use this list for any of the patients in
the study.
Postoperative Protocol
Medications for the treatment of postoperative breakthrough pain included
intravenous morphine, meperidine, and/or oral oxycodone or hydrocodone for all
subjects while they were inpatients. All medications were given on an
as-needed basis. The dose and route of medication were recorded, and the dose
was converted to morphine equivalents. All patients were managed with the
application of an ice pack to the leg in the recovery room. Verbal numeric
rating scores for pain were recorded with each request for analgesia and every
four hours. On the first postoperative day, all patients were discharged to
home with instructions to take oral oxycodone or hydrocodone for the treatment
of breakthrough pain. After discharge, patients recorded the time and amount
of pain medications taken. They also recorded verbal numeric rating scores
with each analgesic dose. These data were recorded for seven days
postoperatively. In addition, all patients underwent the same physical therapy
protocol (see Appendix).
Statistical Methods
All data were analyzed for entry errors, missing data, and consistency
prior to statistical analysis. All data were analyzed with use of descriptive
and inferential statistics. Incidental data were analyzed with use of the
chi-square test. Postoperative analgesic requirements, verbal numeric rating
scores, and quadriceps exercise contraction scores were analyzed with use of
analysis of variance. When analysis of variance demonstrated significant
differences between groups, a post hoc Tukey's Honestly Significant Difference
was performed. Median postoperative analgesic satisfaction scores were
analyzed with use of the Kruskal-Wallis test. A power analysis was performed
with use of the total analgesic requirements from the time of discharge to the
seventh postoperative day. Assuming that a 7-mg difference in morphine
equivalents would be noted between groups with a common standard deviation of
8 mg, the current sample sizes (twenty-five, twenty-one, and nineteen
patients) provided a 76% power with an alpha of 0.05. The level of
significance was set at p < 0.05.
During the study period, 423 anterior cruciate ligament
reconstructions were performed at our facility. Several patients had
multiligamentous injuries, were unwilling to participate, or were managed with
a tourniquet as part of the anterior cruciate ligament reconstruction and
therefore were not included in the study. A total of sixty-five subjects were
enrolled in this study, with twenty-five subjects in the methadone group,
twenty-one subjects in the morphine group, and nineteen subjects in the
control group. No demographic differences were noted between the groups with
regard to age, height, weight, or gender
(Table I). All procedures were
performed with use of autograft from the ipsilateral leg; specifically,
twenty-one procedures were performed with use of bone-tendon-bone graft and
forty-four were performed with use of hamstrings graft.
Inpatient Supplemental Analgesic Requirements
Analysis of the inpatient supplemental analgesic requirements (in morphine
equivalents) demonstrated a significant difference between the groups. The
mean inpatient requirement (and standard deviation) was 10.5 ± 9.3 mg
in the morphine group (Group 2), compared with 21.3 ± 13.3 mg in the
control group (Group 3) and 21.0 ± 15.3 mg in the methadone group
(Group 1) (p = 0.014) (Fig. 1).
With the numbers available, post hoc analysis revealed no difference between
the methadone and control groups (p = 0.998).
Outpatient Supplemental Analgesic Requirements
Analysis of the mean outpatient analgesic requirements also revealed a
significant difference between groups. The mean outpatient requirement (and
standard deviation) was 22.5 ± 16 mg in the morphine group (Group 2),
compared with 35 ± 16.1 mg in the methadone group (Group 1) and 37.1
± 19.6 mg in the control group (Group 3) (p = 0.044). With the numbers
available, post hoc analysis showed no difference between the methadone and
control groups (p = 0.887).
Pain Scores
Analysis of the verbal numeric rating scores for pain revealed only one
time-interval during which the scores were significantly different among the
three groups. Specifically, in the post-anesthesia care unit, upon the
patients' first request for pain medication, the mean pain score (and standard
deviation) was 2.32 ± 3.3 in the morphine group, compared with 3.87
± 3.2 in the methadone group and 5.4 ± 3.4 in the control group.
Post hoc analysis showed a significant difference between the morphine and
control groups (p = 0.031) but not between the methadone and control groups or
between the methadone and morphine groups. No other time-frame (inpatient or
outpatient) demonstrated a significant difference in pain scores.
Complications
There were no complications related to any of the intra-articular
injections.
To our knowledge, the present study represents the first
investigation of the use of intra-articular methadone for postoperative pain
relief. We were unable to prove our hypothesis that methadone, with its long
half-life, would provide improved or prolonged pain relief as compared with
morphine. In fact, no significant differences in supplemental analgesic
requirements or pain scores were observed between the methadone group and the
control group during the entire postoperative course (immediately
postoperatively to seven days postoperatively).
The use of intra-articular morphine following anterior cruciate ligament
reconstruction has been studied previously. In the study by Joshi et
al.1, patients were
managed with the intra-articular administration of 5 mg of morphine (eleven
patients) or saline solution (nine patients) following anterior cruciate
ligament reconstruction. The patients in the morphine group had lower pain
scores and had less of a need for supplemental systemic narcotics in the first
twenty-four hours postoperatively than did the patients in the control group.
Denti et al.3 found
similar results in a study investigating the use of different doses of
intra-articular morphine (1, 2, and 5 mg). The group that received the 5-mg
dose had less of a need for supplemental systemic analgesics in the first
twenty-four hours postoperatively. Brandsson et
al.10 compared
intravenous with intra-articular administration of morphine for postoperative
pain control following anterior cruciate ligament reconstruction performed
with use of bone-tendon-bone autograft. They found that patients who had been
managed with intra-articular morphine, in a 5-mg dose, had better pain relief
and had less of a need for supplemental analgesia when compared with those who
had been managed with an equivalent intravenous dose. Conversely, Reuben et
al.11 failed to
show any difference in pain relief when a 5-mg intra-articular dose of
morphine was compared with a placebo. They hypothesized that multimodal
regimens (intra-articular bupivacaine, perioperative non-steroidal
anti-inflammatory drugs, and cryotherapy), which were used in their study but
not in the previously mentioned studies, provided sufficient analgesia and
that additional intra-articular morphine provided "little additional
benefit." They also believed that, in the presence of perioperative
nonsteroidal anti-inflammatory drugs, intra-articular morphine may not bind
effectively to the intra-articular opioid receptors.
One of the possible reasons that intra-articular methadone was ineffective
may have been that the dosage was too low. As we found no previous reports in
the literature on the intra-articular use of methadone, we relied on
methadone's equianalgesic dosing with morphine (when used systemically) as a
reference point. A 5-mg dose of intra-articular morphine has been well
established as an effective dose following anterior cruciate ligament
reconstruction1,2.
Cepeda et al.5
compared the effects of a 10-mg intra-articular dose of morphine, a 10-mg
subcutaneous dose of morphine, and a 20-mL intra-articular dose of bupivacaine
following various other arthroscopic knee procedures. Both the intra-articular
and the subcutaneous doses of 10 mg of morphine were superior to the
intra-articular dose of bupivacaine, but they were not different from each
other. Ten milligrams is the highest dose of intra-articular morphine that has
been reported in the literature, and Cepeda et al. did not directly compare
this dose with other, more commonly used doses (=5 mg). Still, it is
possible that the use of intra-articular methadone at a higher dose (10 mg)
may provide the prolonged postoperative pain relief that our study was unable
to show in association with a 5-mg dose.
Intra-articular methadone appears to be very safe when given in a 5-mg
dose. In the present study, there were no complications among the twenty-five
patients who received methadone. This is an important finding because it
establishes the safety of intra-articular methadone in the human model. This
may lead to future studies in which varying doses may be explored.
Our study demonstrated that intra-articular morphine in a 5-mg dose was
very effective for reducing the need for supplemental narcotics. This effect
was significant only for the first twenty-four hours postoperatively. We also
used multimodal regimens, which included perioperative nonsteroidal
anti-inflammatory drugs (ketorolac, ibuprofen, and naproxen), intra-articular
bupivacaine, and cryotherapy. In addition, we did not use a tourniquet during
any of the procedures. We thought that a tourniquet could be a separate cause
of postoperative pain that may vary depending on the duration of inflation.
Arthroscopic anterior cruciate ligament reconstruction with either a
bone-tendon-bone or hamstrings autograft is a procedure that we routinely
perform without the use of a tourniquet. By studying only patients in whom a
tourniquet was not used, we believe that we have eliminated one of the many
variables associated with postoperative pain.
While we used both hamstrings and bone-tendon-bone autografts in this
study, we found no difference with regard to postoperative pain when similar
groups of patients who had received these two types of grafts were compared on
the basis of the injectate (morphine, methadone, or placebo).
In conclusion, intra-articular methadone was not effective for providing
improved or prolonged pain relief following anterior cruciate ligament
reconstruction. However, a 5-mg dose of intra-articular morphine appears to be
safe and effective for providing postoperative pain relief, and it is our
current treatment of choice.
Tables presenting the general anesthesia protocol and the postoperative
physical therapy protocol are available with the electronic versions of this
article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?
Note: The authors thank Darwin M. Brooks, CRNA, MS, Pamela
Tucker, PT, MS, and Charles Vacchiano, CRNA, PhD, for their assistance with
this project.
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