Full text of DOI:10.1007/BF03020377

REGIONAL ANESTHESIA AND PAIN
1109
Methadone is safe for treating hospitalized
patients with severe pain
[La méthadone est sans danger chez les patients hospitalisés qui éprouvent des
douleurs intenses]
Yoram Shir MD, Gila Rosen RN, Alexander Zeldin MD, Elyad M. Davidson MD
Purpose: Methadone is still regarded as a second line opioid for
patients suffering from severe pain, and is rarely used in hospitalized
patients. The infrequent use of methadone is probably due to its
long plasma half-life that could lead to accumulation and toxicity. In
the present study we report that clinically effective analgesic doses
of methadone, given either epidurally or orally, can be used safely
for prolonged treatment in hospitalized patients.
Hadassah Hospital de Jérusalem. Parmi eux, 12 % avaient moins de
17 ans. L’analgésie a été satisfaisante chez plus de 85 % des patients.
Aucun effet secondaire important n’a été rapporté avec l’usage de la
méthadone orale. Trois patients traités avec la méthadone épidurale
(0,09 %) ont subi une dépression respiratoire significative. Une défail-
lance de la pompe épidurale ou une erreur de programmation avaient
alors provoqué des surdoses de méthadone. Aucun enfant ou adulte
traité avec la méthadone n’est devenu dépendant du médicament
pendant l’hospitalisation.
Clinical features: Over a five-year period we administered
methadone at Hadassah Hospital in Jerusalem to 3,954 in-patients
with severe pain, 12% of whom were younger than 17 yr.
Satisfactory pain relief was recorded in more than 85% of the
patients. None of the patients treated with oral methadone devel-
oped serious side effects. Three patients, treated with epidural
methadone (0.09%), developed a clinically significant respiratory
depression. In all three cases, epidural pump failure or pump mis-
programming resulted in methadone overdose. None of the chil-
dren or adults treated with methadone developed addiction during
hospitalization.
Conclusion : Étant donné ses propriétés analgésiques et son remar-
quable profil d’innocuité, nous croyons que la méthadone pourrait s’a-
jouter à l’arsenal thérapeutique des patients hospitalisés. Elle peut aussi
servir d’opioïde de premier choix chez certains patients hospitalisés.
NDERTREATMENT of pain is com-
mon in hospitalized patients, children
and adults.1, 2It is estimated that 50% of
Conclusion: Based on its analgesic properties and marked safety
profile, we suggest that methadone could be added to the analgesic
armamentarium of in-hospital health-care providers. Moreover,
methadone could serve as the opioid of first choice in some in-
patient populations.
U
in-patients suffer substantial pain at some
time.2 Although patients undergoing surgical proce-
dures are more likely to suffer pain during hospitaliza-
tion, more than 20% of non-surgical patients report
substantial pain while in hospital.2, 3
Opioids are the mainstay of therapy for pain due to
malignancy and an important adjuvant in patients with
pain of non-cancerous etiology. Nevertheless, almost
50% of in-patients that do receive opioids for their
pain report moderate to severe pain.4
Objectif : La méthadone est toujours considérée comme un opioïde
mineur dans les cas de douleurs intenses. Elle est rarement prescrite
aux patients hospitalisés. Cette situation est sans doute reliée à sa
longue demi-vie plasmatique qui peut entraîner accumulation et toxi-
cité. Nous montrons ici que des doses analgésiques efficaces de
méthadone, administrées par voie épidurale ou orale, peuvent être
utilisées sans danger comme traitement prolongé de patients hospita-
lisés.
Methadone is a potent, highly lipid soluble and
protein bound synthetic opioid, with a rapid onset of
analgesia, large volume of distribution and prolonged
half-life.5 While its analgesic effect during chronic
treatment does not exceed 12 hr, its plasma half-life
could be as long as 72 hr.6 Although favourable results
Éléments cliniques : Pendant cinq ans, nous avons administré de
la méthadone pour douleurs intenses à 3 954 patients hospitalisés au
From the Pain Relief Unit, Department of Anesthesiology and Critical Care Medicine, Hadassah University Hospital, Jerusalem, Israel.
Address correspondence to: Dr. Yoram Shir, Pain Relief Unit, Department of Anesthesiology, Hadassah University Hospital, Jerusalem
91120, Israel. Phone: +9722-6776911; Fax: +9722-6429392; E-mail: yshir@hadassah.org.il
Accepted for publication July 5, 2001.
Revision accepted August 29, 2001.
CAN J ANESTH 2001 / 48: 11 / pp 1109–1113

1110
CANADIANJOURNAL OF ANESTHESIA
were reported with methadone in the perioperative
setting7–9 and in patients with chronic pain,1 0 its in-
hospital use is limited. This is probably due to several
cases of serious side effects that were reported with
methadone, when large doses were frequently admin-
istered,11–13 leading to gradual accumulation and toxic
levels.1 4 At Hadassah Hospital in Jerusalem, however,
methadone has been increasingly prescribed over the
last two decades for patients with severe pain, mainly
via the epidural and oral routes. We use epidural
methadone to relieve postoperative15,16 or chronic
pain conditions,1 7whereas oral methadone is given for
patients capable of oral intake, suffering persistent or
chronic pain.1 8
with moderate pain), the methadone dose was
reduced to 0.2 mg·kg–1·day–1 48 hr after treatment
began. Previous reports showed that plasma
methadone levels in patients treated by epidural
methadone in this dose range were within its analgesic
range.1 6 Indications for terminating epidural
methadone treatment included: (a) unrelieved severe
or excruciating pain; (b) when epidural treatment was
no longer indicated; (c) significant side effects, includ-
ing urinary retention, itching, nausea and vomiting,
mental clouding and respiratory depression; and (d)
infection at the site of epidural catheter insertion, with
or without meningeal or systemic involvement. The
duration of epidural methadone treatment was not an
indication for its discontinuation.
More than 5,000 hospitalized patients received
methadone at our hospital since 1995. The aim of this
retrospective study was to examine its safety in a large
patient population.
Protocol of oral methadone treatment
Oral, racemic 0.1% methadone in glycerine was given
to patients of all ages with severe persistent or chron-
ic pain, capable of oral intake. Enrolled were patients
fulfilling one of the following criteria: (a) pain that was
not alleviated by non-opioid or other opioid medica-
tions; (b) significant side effects with other opioids;
and (c) patients suffering from burn pain or pain due
to peripheral vascular disease, where methadone
served as the opioid of choice.
Methods
Data collection
Since January 1995, details of every patient treated by
our in-hospital pain service were compiled in an elec-
tronic data base. These data include demographics,
diagnosis, average daily pain scores, type and dose of
analgesic drugs, other medical treatment, length of
treatment and resulting complications including respi-
ratory depression, sedation, itching, nausea and urinary
retention. Patients’ data were updated twice daily by the
nursing and medical staff of the pain service and stored
in the hospital’s central database. For the purpose of the
current survey, data of all hospitalized patients, labelled
as treated with either “oral methadone” or “epidural
methadone” between January 1995 and December
1999 were pooled. No hospitalized patient that
received oral or epidural methadone during that time
period was excluded from the study.
ORAL METHADONE I N CHILDREN
In infants and children younger than 10 yr, the initial
daily dose of methadone did not exceed 0.2–0.4
mg·kg–1·day–1, bid–tid. When indicated, the methadone
dose could be escalated daily, reaching a maximal
allowed dose of 1 mg·kg– 1·day–1.18 Oral methadone was
used routinely in children with cancer, after trauma and
following burn injury.
ORAL METHADONE I N ADULTS
In opioid-naive adults, the initial methadone dose did
not exceed 5–10 mg bid–tid, and was titrated careful-
ly, according to the clinical response and side effects.
These daily doses were reported previously to alleviate
pain in chronic pain patients, with plasma levels well
within methadone’s analgesic range.5 Infrequently,
larger initial methadone doses (up to 15 mg tid) were
prescribed for patients with intractable pain, not
relieved by other opioid medications. The methadone
dose was escalated in 20–30% increments according to
clinical response and side effects, with no ceiling limi-
tation. Oral methadone treatment was discontinued if
pain persisted or when accompanied by significant side
effects.
Protocol of epidural methadone treatment
Methadone (0.1% in 10% glucose in children, or 0.2%
in 10% glucose in adults) has been our opioid of
choice for epidural analgesia in patients aged five years
and older. Methadone was given epidurally to patients
suffering from postoperative pain, pain following trau-
ma, cancer pain, persistent or chronic low back pain
and pain due to peripheral neuropathies and peripher-
al vascular disease. Following a methadone loading
dose of 0.6 mg·10 kg–1, a combination of bupivacaine,
0.125–0.25%, with methadone, in an initial daily dose
not exceeding 0.3 mg·kg–1, was infused continuously,
using battery operated infusion pumps (Graseby,
Medical M26, U.K.) or PCA syringe pumps (P5000,
IVAC, U.K.). Unless otherwise indicated (patients

Shir et al.: IN-HOSPITAL SAFETY OF METHADONE
1111
TABLE In-hospital pain treatment with methadone: age distribution, etiology and length of treatment
Age
Epidural methadone
Oral methadone
group (yr)
Patients with
postoperative
pain
Patients with
non-surgical
pain
Length of
treatment
(days: median-
range)
Patients with Patients with Patients with
Length of
treatment
cancer pain
burn pain
other non-
malignant pain (days: median-
range)
male
female
male
female
male female male female male female
1–9
117
75
54
51
0
1
1
1
2 (1–7)
3 (1–19)
3 (1–14)
3 (1–17)
4 (1–32)
3 (1–7)
3 (1–9)
4 (1–35)
3 (1–35)
9
7
7
4
14
19
24
8
11
7
6
2
8
25
16
10
57
26
12
9
5
3
40
11
8
4
7
3
1
3
4
7
3
5
1
2
1
2
6 (1–17)
8 (2–40)
7 (1–21)
6 (1–34)
8 (3–97)
8 (3–23)
7 (1–34)
6 (1–19)
7(1–97)
10–17
18–29
30–39
40–49
50–59
60–69
Over 70
Total
119
115
141
185
327
315
267
393
269
223
246
179
20
24
49
49
29
47
13
19
37
40
36
40
6
3
19
14
29
17
13
17
3
0
3036
406
177
192
143
Scoring scale
oral methadone for eight days. Sixteen percent of the
patients were older than 70, treated for time periods
as long as 35 days. The oldest was an 81-yr-old male
patient with lower limb ischemia treated with epidur-
al methadone for 14 days.
Average daily pain scores were recorded using a ver-
bal, five-point scale (none, mild, moderate, severe or
excruciating). For sedation scoring we also used a five-
point scale (patient fully alert – patient not arousable).
Respiratory depression was defined as respiratory rate
<8·min–1 in adults, <12–16 in children aged three to
ten and <20·min– 1 in children younger than two.
Itching and nausea were recorded using a five-point
verbal scale (none – intolerable).
Epidural methadone
Acceptable pain relief (none, mild or moderate pain
scores) was reported by more than 90% of the patients.
Three patients (0.09%), receiving methadone for post-
operative pain, developed a clinically significant respira-
tory depression, all within 36 hr of surgery. These
patients recovered completely once methadone was dis-
continued. In all three cases epidural pump failure or
pump maladjustment resulted in methadone overdose.
One of these patients, a 36-yr-old male patient after
thoracic surgery, accidentally received 35 mg of
methadone via a high thoracic epidural catheter within
18 hr. This dose was due to a misprogramming of the
pump. The other two patients received their daily dose
of methadone over four to six hours due to electronic
pump failure. Six chronic pain patients (0.17%) devel-
oped clinically significant deep tissue or epidural infec-
tion. One of these patients required a surgical
laminectomy for epidural abscess evacuation. No resid-
ual neurological deficit was recorded in any of these
patients. Methadone treatment via the epidural route
had to be discontinued in 7% of patients due to mental
obtundation, itching, nausea or urinary retention.
Monitoring
Respiration, heart rate and sedation scores were mon-
itored every four hours in children. Oxygen saturation
was monitored continuously in children treated with
epidural, but not oral methadone. Blood pressure, res-
piration, heart rate and sedation scores were moni-
tored in adults every four to eight hours. Oxygen
saturation was not monitored routinely in adults.
Supplementary oxygen was not prescribed routinely,
unless indicated for individual patients.
Results
From January 1995 to December 1999, 10,389
patients were treated by the in-hospital pain service.
Of these, 3,954 patients (26%) from 22 surgical and
non-surgical wards were treated with methadone.
Epidural methadone was used in 3,442 patients (87%)
while 512 patients were treated with oral methadone
(Table). Twelve percent of patients treated with
methadone were children younger than 17, with a
mean age of 4.1 yr. The youngest child receiving
methadone was a ten-month-old female with burns
covering 25% of her body surface area, who received
Oral methadone
Acceptable pain relief was recorded for more than 85%
of the patients treated with oral methadone. The
range of oral dose of methadone in children was

1112
CANADIANJOURNAL OF ANESTHESIA
0.1–1.1 mg·kg– 1·day–1. However, only 12 children
(7%), suffering from cancer pain or pain after trauma,
required daily methadone doses exceeding 0.6
mg·kg– 1. The range of oral methadone in adults was
10–110 mg·day– 1. However, only 12 (6%) required
daily methadone doses exceeding 60 mg. None of the
children or adults treated with oral methadone devel-
oped respiratory depression or severe mental obtun-
dation. Minor side effects (mental obtundation,
itching, nausea and urinary retention), necessitating
the substitution of oral methadone by another opioid,
were recorded in 13% of the patients. No document-
ed cases of addiction to methadone were recorded.
Weaning from treatment with oral methadone was
uneventful in all 182 methadone-treated children.
in blood concentrations in patients treated chronically
with methadone are lower than with other opioids,22
its long plasma half-life may lead to intoxication.5
However, when adhering to the recommendations for
chronic methadone treatment in adults, where initial
doses of 5–10 mg are given every eight hours with
gradual prolongation of this interval,19,20 the risk of
overdose decreases significantly. In support of this
conclusion, the present survey shows that the vast
majority of patients treated according to these guide-
lines did not develop serious side effects.
More than 180 children were treated with oral
methadone with no serious complications. Few
reports have described the use of methadone in chil-
dren. Most of these studies were conducted in the
acute postoperative pain setting,8 while only three
described the use of oral methadone in children with
chronic pain.18,23,24 In contrast to adults, however,
pharmacokinetic studies of methadone in children are
not available. Thus, we chose to limit the daily dose of
methadone in children to 1 mg·kg– 1. The lack of sig-
nificant side effects in the present report indicates
that, at this dose range, methadone is safe in hospital-
ized infants and children.
Albeit its long plasma half-life after repeated admin-
istration, methadone possesses other unique proper-
ties, making it suitable for treating patients with severe
pain. It is inexpensive, well absorbed from the gas-
trointestinal tract (with up to 100% bioavailability),
has a rapid onset of analgesic effect, appears to have no
active metabolites and its clearance is probably not
affected by hepatic or renal disease.5 Methadone has
also antagonist activity at the N-methyl-D-aspartate
(NMDA) receptor.2 5 NMDA receptors are involved,
among other functions, in neuropathic pain syn-
dromes and in the development of opioid tolerance.
Hence, methadone could be of special value in these
patients.
We conclude that methadone, administered either
epidurally or orally, is effective and safe for treating
hospitalized children and adults suffering from acute
or chronic pain. When administered according to
strict guidelines, respiratory depression and other sig-
nificant side effects were infrequent in nearly 4,000
patients. Several physicians hesitate to use methadone
in hospitalized patients. Yet, when considering its safe-
ty profile, we suggest that methadone should be
added to the analgesic armamentarium of in-hospital
health-care providers.
Discussion
To our knowledge, this clinical report is the first large-
scale survey examining the safety of methadone in
hospitalized patients. We show that methadone, in
doses previously reported to alleviate pain16,19,20 is safe
in hospitalized patients suffering from acute or chron-
ic pain. None of the patients treated with oral
methadone, and only nine out of more than 3,400
patients treated with epidural methadone developed
serious, life threatening side effects. Six patients in the
epidural group developed infection, probably not
related to methadone, whereas the other three devel-
oped respiratory depression, resulting from human
error or pump failure. Thus, none of the patients
receiving epidural methadone according to protocol
developed respiratory depression.
Our results with epidural methadone are compatible
with most previous studies where epidural methadone
was used in pain patients. Not a single case of mortality
or significant respiratory depression has been reported
previously with epidural methadone after surgery or in
chronic pain patients. This is probably due to
methadone’s lipophilicity that, in clinically relevant
doses, induces its complete clearance from the cere-
brospinal fluid before reaching the cisterna magna.21
Methadone possesses a dual analgesic effect when
administered epidurally: a direct effect, through spinal
mechanism, and a central effect, following its systemic
accumulation.9,16 However, limiting the daily dose of
epidural methadone to 0.3 mg·kg–1 initially and
decreasing the dose after 48 hr prevent plasma accumu-
lation. The three cases of respiratory depression report-
ed here were all due to an accidental administration of
methadone in doses significantly higher than planned.
Sporadic cases of methadone overdose, resulting in
respiratory depression after oral administration, have
been reported previously. Although daily fluctuations
References
1 Schechter NL. The undertreatment of pain in children:
an overview. Pediatr Clin North Am 1989; 36: 781–94.

Shir et al.: IN-HOSPITAL SAFETY OF METHADONE
1113
2 Abbott FV, Gray-Donald K, Sewitch MJ, Johnston CC,
Edgar L, Jeans ME. The prevalence of pain in hospital-
ized patients and resolution over six months. Pain
1992; 50: 15–28.
17 Shir Y, Yehuda Ben DB, Polliack A, Magora F.
Prolonged continuous epidural methadone analgesia in
the treatment of back and pelvic pain due to multiple
myeloma. Pain Clin 1987; 1: 255–8.
3 Donovan M, Dillon P, McGuire L. Incidence and char-
acteristics of pain in a sample of medical-surgical inpa-
tients. Pain 1987; 30: 69–78.
4 Owen H, McMillan V, Rogowski D. Postoperative pain
therapy: a survey of patients’ expectations and their
experiences. Pain 1990; 41: 303–7.
5 Fainsinger R, Schoeller T, Bruera E. Methadone in the
management of cancer pain: a review. Pain 1993; 52:
137–47.
6 Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley
KM. Pharmacokinetics and pharmacodynamics of
methadone in patients with chronic pain. Clin
Pharmacol Ther 1987; 41: 392–401.
7 Gourlay GK, Willis RJ, Lamberty J. A double-blind
comparison of the efficacy of methadone and morphine
in postoperative pain control. Anesthesiology 1986;
64: 322–7.
8 Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna
NF. Comparison of morphine and methadone for pre-
vention of postoperative pain in 3-to-7 year-old chil-
dren. J Pediatr 1991; 119(Pt 1): 136–41.
18 Shir Y, Shenkman Z, Shavelson V, Davidson EM, Rosen
G. Oral methadone for the treatment of severe pain in
hospitalized children: a report of five cases. Clin J Pain
1998; 14: 350–3.
19 Sawe J, Hansen J, Ginman C, et al. Patient-controlled
dose regimen of methadone for chronic cancer pain.
BMJ 1981; 282: 771–3.
20 Paalzow L, Nilsson L, Stenberg P. Pharmacokinetic basis
for optimal methadone treatment of pain in cancer
patients. Acta Anaesthesiol Scand Suppl 1982; 74:
55–8.
21 Payne R, Inturrisi CE. CSF distribution of morphine,
methadone and sucrose after intrathecal injection. Life
Sci 1985; 37: 1137–44.
22 Gourlay GK, Cherry DA, Cousins MJ. A comparative
study of the efficacy and pharmacokinetics of oral
methadone and morphine in the treatment of severe
pain in patients with cancer. Pain 1986; 25: 297–312.
23 Martinson IM, Nixon S, Geis D, YaDeau R, Nesbit M,
Kersey J. Nursing care in childhood cancer: methadone.
Am J Nurs 1982; 82: 432–5.
9 Wang JM, Knarr DC, Raj PP, Denson D. Continuous
epidural methadone for the management of postopera-
tive pain after lower abdominal surgery. Reg Anesth
1992; 17: 26–8.
10 Ripamonti C, Zecca E, Bruera E. An update on the
clinical use of methadone for cancer pain. Pain 1997;
70: 109–15.
11 Ettinger DS, Vitale PJ, Trump DL. Important clinical
pharmacologic considerations in the use of methadone
in cancer patients. Cancer Treat Rep 1979; 63: 457–9.
12 Hunt G, Bruera E. Respiratory depression in a patient
receiving oral methadone for cancer pain. J Pain
Symptom Manage 1995; 10: 401–4.
24 Miser AW, Miser JS. The use of oral methadone to con-
trol moderate and severe pain in children and young
adults with malignancy. Clin J Pain 1986; 1: 243–8.
25 Gorman AL, Elliott KJ, Inturrisi CE. The d- and l- iso-
mers of methadone bind to the non-competitive site
on the N-methyl-D-aspartate (NMDA) receptor in rat
forebrain and spinal cord. Neurosci Lett 1997; 223:
5–8.
13 Oneschuk D, Bruera E. Respiratory depression during
methadone rotation in a patient with advanced cancer.
J Palliat Care 2000; 16: 50–4.
14 Olsen Gd, Wendel HA, Livermore JD, Leger RM, Lynn
RK, Gerber N. Clinical effect and pharmacokinetics of
racemic methadone and its optical isomers. Clin
Pharmacol Ther 1977; 21: 147–57.
15 Evron S, Samueloff A, Simon A, Drenger B, Magora F.
Urinary function during epidural analgesia with
methadone and morphine in post-cesarean section
patients. Pain 1985; 23: 135–44.
16 Shir Y, Eimerl D, Magora F, Damm D, Schulte-
Monting J, Chrubasik J. Plasma concentrations of
methadone during postoperative patient-controlled
extradural analgesia. Br J Anaesth 1990; 65: 204–9.