S72 Journal of Pain and Symptom Management Vol. 29 No.

5S May 2005

Proceedings of the Symposium “Updates of the Clinical Pharmacology

of Opioids with Special Attention to Long-Acting Drugs”

Recent Developments
in Patient-Controlled Analgesia
Klaus A. Lehmann, MD, PhD
Department of Anesthesiology, University of Cologne, Cologne, Germany

Abstract
Patient-controlled analgesia (PCA) has become the gold standard for acute pain
management since it was first introduced 20 years ago, and its merits have been discussed
in quite a large number of publications. This review summarizes the more recent
developments, such as new application devices and strategies, including intranasal,
spinal, and regional PCA; patient-controlled sedation; experience with children and elderly
people; and some data from chronic pain situations. Analyzing PCA literature from 2001
onwards confirms the author’s long belief that the PCA principle (“WYNIWYG”: what you
need is what you get) was the most important aspect of a patient-controlled strategy, more
or less independent of the type of drug or machine. Discovering this principle has changed
the understanding of pain and suffering. J Pain Symptom Manage 2005;29:
S72–S89. 쑖 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All
rights reserved.

Key Words
Analgesia, acute and chronic, patient-controlled, analgesics, opioids, local anesthetics,
safety aspects, mishaps, cost-benefit considerations

Introduction cause “these methods do not take into account

Twenty years ago, in June 1984, a small group
of enthusiasts met in Leeds Castle, UK, for the
first International Workshop on Patient-Con-
trolled Analgesia.1 We were convinced “that the
present methods of routinely prescribing a vari-
ety of analgesic drugs given either intramuscu-
larly or subcutaneously, and occasionally by
mouth if the surgical conditions permits, were
not satisfactory in controlling pain and provid-
ing comfort for postoperative patients,” be-
Address reprint requests to: Klaus A. Lehmann, MD,
PhD, Department of Anesthesiology, University of
Cologne, Joseph-Stelzmann-Strasse 9, D-50924 Köln,
Germany.
Accepted for publication: January 5, 2005.
the very large variability of the responses of
patients, and are all dependent upon the inter-
pretation of nurses of prescriptions by physi-
cians.” Among the topics we discussed at that
time were the use of patient-controlled analge-
sia (PCA) for research (analgesic drugs and
analgesia, variability in patient characteristics,
pharmacokinetics and pharmacodynamics, bio-
feedback systems), as well as early clinical expe-
rience with application strategies, routes of
administration, and various opioids. None of us
expected PCA to become the gold standard of
acute pain management, or—even more im-
portant—to change our understanding of pain
and suffering. PCA later influenced the concept
of acute pain services; the introduction of
treatment modalities for conscious sedation,

쑖 2005 U.S. Cancer Pain Relief Committee 0885-3924/05/$–see front matter

Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2005.01.005
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
regional anesthesia, and labor; and the develop-
ment of treatments for children, cancer pa-
tients, and chronic pain patients. Up to now,
more than 1,700 papers have been published
on the use of PCA, including nearly 200 reviews
and three meta-analyses.2–4
This update will primarily discuss the most
recent developments in postoperative pain and
highlight the variability of drug use patterns in
PCA for acute and cancer pain. It will
concentrate on articles published since 2001.
Space restriction prevents in-depth discussion
of methodology or quality of results (readers
are referred to newer reviews on safety and effi-
cacy5,6 or drug interactions7). The author’s
main interest is to outline the shift from early
expectation to today’s routine. This includes
the discussion of patients’ attitudes towards
PCA, its efficacy and safety compared with other
strategies, and newer application modes and
indications.
PCA Principle and the WYNIWYG
Concept
The name of the game is individual variabil-
ity.8 PCA deals with this problem by allowing
individual titration. Analgesic consumption
may be huge, with an average much higher
than earlier thought possible. Patients’ accep-
tance is overwhelming, because they no longer
have to wait for compassionate nurses or doc-
tors to provide analgesia (although the impor-
tance of self-control has been questioned
recently9), and the staff can learn from patients
how to individualize analgesic needs. The in-
sight that thresholds are unpredictable in indi-
vidual patients (both subjective and objective
parameters such as plasma concentrations) is
one of the greatest merits of PCA. Any tech-
nique based on this knowledge and committed
to immediate reaction (the “PCA principle”)
can in theory be considered equivalent. It
became more and more evident that different
PCA modes (by any route or device) are not
universally superior to nurse-controlled tech-
niques. Low-cost techniques based on the
“WYNIWYG (what you need is what you get)
concept” have been shown to be equally effec-
tive. In my opinion, PCA was of utmost impor-
tance until the PCA principle was discovered.
Even those who have no (or not enough) PCA
S73
devices available can apply the WYNIWYG strat-
egy. This involves trusting the patient, providing
adequate monitoring and appropriate docu-
mentation, and, of course, raising the educa-
tional level of the staff on surgical wards.
Efficacy of PCA in Comparison
with Other Pain Relieving Techniques
Walder et al., in a recent meta-analysis, ana-
lyzed 32 trials in which morphine, pethidine
(meperidine), piritramide, nalbuphine, or tra-
madol had been administered either by PCA
or intramuscularly, intravenously, or subcutane-
ously. The evidence shows that, in the post-
operative setting, opioid PCA, compared with
conventional opioid treatment, improves anal-
gesia and decreases the risk of pulmonary com-
plications. Patients prefer PCA.2
Dolin et al. collected pooled postoperative
pain scores from 165 publications and con-
cluded that the mean incidence of moderate
to severe pain was 67.2% and that of severe pain
29.1% for intramuscular opioids. The corres-
ponding values were 35.8% and 10.4% for PCA,
and 20.9% and 7.8% for epidural analgesia,
respectively.3
Comparing epidural infusion or continuous
femoral block with local anesthetics and intrave-
nous morphine PCA in 56 patients, Capdevila
et al. found significantly lower pain scores at
rest and during passive motion for both re-
gional anesthesia groups. Early postoperative
knee mobilization following epidural infusion
and femoral block was significantly better
than with PCA, and average durations of stay
in the rehabilitation center significantly
shorter: 37–40 days after epidural or femoral
block compared with 50 days in the morphine
PCA group. Side effects, however, were encoun-
tered more frequently with epidural infusion.10
Similar results were obtained by Chelley et al.
with 92 arthroplasty patients, where 3-in-1 and
sciatic blocks followed by femoral infusion with
local anesthetics significantly reduced post-
operative morphine requirement by 74% com-
pared with intravenous PCA, and by 35%
compared with epidural analgesia. The blocks
also provided better recovery, were associated
with reduced postoperative bleeding and al-
lowed better performance on continuous pas-
sive motion, which led to a 20% decrease in the
length of hospitalization.11
S74
Direct continuous local wound perfusion of
0.5% bupivacaine for 60 hours was as effective as
intravenous morphine PCA for postoperative
pain relief in 70 patients after laparotomy for
major colorectal surgery, with no significant dif-
ference in pain scores at rest and movement,
except for pain at rest on the first postoperative
day, when PCA scored slightly better.12 In a
group of 114 patients undergoing gastric bypass
surgery as a treatment for obesity, the combina-
tion of effective preincision local anesthetic in-
filtration, preextubation supplemental field
infiltration (each with bupivacaine) and post-
operative intravenous morphine PCA produced
lower pain scores than thoracic epidural analge-
sia with bupivacaine and pethidine or intra-
venous morphine PCA without pretreatment.13
In another trial, patient-controlled epidural an-
esthesia (PCEA) with bupivacaine and fentanyl
provided better pain relief than continuous
intra-articular local anesthetic infusion in 168
patients recovering from knee surgery.14
More and more studies do not only address
postoperative pain intensity but also the influ-
ence that pain might have on recovery and/
or chronification. Results are often conflicting,
but most investigations show a trend for better
outcome when spinal application is used in-
stead of intravenous routes, and that local anes-
thetics are more effective than opioids. One
possible reason why improved outcome is often
so difficult to demonstrate is that pain manage-
ment strategies are not yet sufficiently in-
tegrated with overall perioperative care and
postoperative rehabilitation.15
Sentürk et al. found a 62% incidence of
chronic pain after thoracotomy, with an in-
crease to 83% in patients who experienced
pain on the second postoperative day. In their
69 patients, pain was better controlled by tho-
racic epidural analgesia with preoperative initi-
ation (using bupivacaine and morphine),
followed by postoperative PCEA with the same
drug combination, than by intravenous mor-
phine PCA alone. The authors concluded that
preoperatively initiated thoracic epidural anal-
gesia had the most satisfying results in con-
trolling postthoracotomy pain in the acute and
long-term period, and that it was associated
with a decreased incidence (and intensity) of
chronic pain compared with postoperative (epi-
dural or intravenous) analgesia.16 Ochroch
Lehmann Vol. 29 No. 5S May 2005
et al., on the other hand, did not find any differ-
ence in the incidence of long-term chronic pain
after thoracotomy, with either intraoperative
epidural bupivacaine and fentanyl or placebo,
although early analgesic consumption was
significantly reduced in the former group.17
Pulmonary outcomes was not influenced in
54 patients with lung cancer undergoing thora-
cotomy who received postoperatively con-
tinuous epidural infusion (ropivacaine with
sufentanil) or intravenous morphine PCA.
Both techniques provided good analgesia at
rest, but PCA was less effective during mobiliza-
tion. Postoperative respiratory function and ar-
terial blood gas values were reduced compared
with preoperative values, but without significant
differences between groups at any time, and CT
scans revealed comparable amounts of atelecta-
sis.18 Efficacy of intravenous morphine PCA
after thoracotomy could be significantly in-
creased by presurgical lumbar intrathecal
injection of 0.5 mg morphine and/or 50 µg
sufentanil.19
When compared with continuous postopera-
tive, intravenous pain therapy or PCA, intra- and
postoperative thoracic epidural anesthesia
using bupivacaine and fentanyl significantly re-
duced the length of stay in the intensive care
unit, the administration of antibiotics, days
without oral nutrition, and the rate of anasto-
mosis insufficiencies in a group of 175 patients
with gastrointestinal carcinoma. Epidural an-
esthesia also led to less frequent vomiting and
earlier resumption of gastrointestinal motility.
However, these positive effects did not have
a significant beneficial impact on overall
hospitalization.20
Carli et al. randomized 64 patients under-
going elective colonic resection to either intra-
venous morphine PCA or thoracic epidural
analgesia with bupivacaine and fentanyl. The
superior quality of pain relief provided by epi-
dural analgesia had a positive impact on out-
of-bed mobilization, bowel function, and intake
of food, with long-lasting effects on exercise ca-
pacity and health-related quality of life. Length
of hospital stay and incidence of complications
were similar in both groups, although patients in
the epidural group were ready to be discharged
earlier.21 These results are in accordance with
a previous report on 42 patients by the same
group.22 Paulsen et al., on the other hand, con-
firmed superior pain control with thoracic epi-
dural analgesia (bupivacaine/fentanyl), but did
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
not find significant advantages over intravenous
morphine or pethidine PCA with respect to
return of bowel function in 49 patients after
bowel resection, again with no difference in
discharge times. This might have been caused
by a higher incidence of complications (fever,
urinary retention, urinary tract or wound infec-
tion, and oversedation) in the epidural group
(61% vs. 29%).23 Quality of analgesia, particu-
larly on coughing, and sleep could be signifi-
cantly improved in gastrectomy patients who
had thoracic PCEA (bupivacaine and fentanyl)
supplemented by slow continuous infusion
during the nights.24
In 168 patients undergoing surgery of the
abdominal aorta, thoracic epidural anesthesia
combined with light general anesthesia and fol-
lowed by either intravenous or epidural PCA
offered no major advantage or disadvantage
when compared with general anesthesia
alone followed by either intravenous or epi-
dural PCA. Although PCEA was associated with
a significantly shorter time to extubation, post-
operative pain scores and outcomes were simi-
lar among the four treatment groups with
respect to death, myocardial infarction, myocar-
dial ischemia, reoperation, pneumonia, and
renal failure. Length of hospitalization and
direct medical costs for patients surviving to
discharge were also comparable.25
Intra- and postoperative thoracic epidural an-
algesia (ropivacaine and morphine) compared
with intravenous morphine PCA offered signifi-
cantly improved pain control after breast recon-
struction in 18 patients investigated by Correll
et al. Time to first ambulation, to first bowel
sounds, to tolerating oral nutrition, incidence
of nausea/vomiting or pruritus, and time to first
flatus were not statistically different between the
groups, but the epidural technique resulted in
a 25-hour reduction in time of hospitalization.26
Chen et al. performed a direct comparison
of epidural and intravenous pethidine PCA in 37
patients after total gastrectomy. Pain scores,
side effects (nausea, vomiting, pruritus, and
sedation), patient satisfaction, and length of
hospital stay were similar between the groups.
Mean cumulative pethidine consumption in the
first 24 hours was 33% less in the epidural than
in the intravenous group, although most of this
difference occurred in the first 8 postoperative
hours.27 Similar results were found in a study
S75
with 240 obstetric patients, where both intrave-
nous and epidural PCA had excellent analgesic
effect. Urinary retention was less and sedation
higher with intravenous PCA, and recovery of
bowel movement faster with PCEA.28
Multimodal analgesia (a combination of epi-
dural opioid/local anesthetic and systemic ket-
orolac for 48 hours) allowed significantly better
pain control at rest and coughing, compared
with intravenous fentanyl or morphine PCA in
47 intravenous nutrition patients recovering
from major upper abdominal surgery. Only the
multimodal analgesia group maintained total
body protein and fat. Nitrogen balance and the
hormonal response to surgery were not consis-
tently influenced by the treatment modality.29
In a systematic review of 9 studies (including
640 patients) to compare efficacy and safety of
PCEA and continuous epidural labor anesthesia
with local anesthetics, van der Vyver et al. con-
cluded that fewer anesthetic interventions were
necessary for PCEA, which also received less
local anesthetic and therefore developed less
motor block. Both methods were safe for mother
and newborn.4 When local anesthetics were
compared with opioids in women with severe
eclampsia, epidural analgesia using bupiva-
caine and fentanyl provided significantly better
pain relief than intravenous pethidine PCA. Pa-
tients who received epidural analgesia needed
ephedrine more often for the treatment of hy-
potension, but their infants were less likely to
need naloxone at delivery (9% vs. 54%). Com-
pared with intravenous opioid PCA, intrapar-
tum epidural analgesia did not significantly
increase the cesarean delivery rate.30 Epidural
PCA after cesarean section with a mixture of
0.06% bupivacaine and sufentanil was more
effective than intrathecal 0.15 mg morphine and
paracetamol/tramadol supplementation.31
New Devices and Application
Strategies
Optimal application modes for PCA were
discussed from the very beginning. Over the
years, it became evident that continuous, that
is, demand-independent background infusions
usually did not improve the quality of analgesia
but increased overall opioid consumption with
the risk of higher incidences of respiratory de-
pression32—a result which was recently re-
confirmed in a study with nalbuphine PCA.33
S76
“Best” demand doses seem to exist for each
opioid with respect to immediate onset of
action, efficacy, and control of side effects.34
Variable dose PCA, as recommended by Owen
et al.,35,36 where patients have the choice be-
tween three demand buttons delivering 0.5–1.5
mg of morphine, are obviously only seldom used.
The concept of pharmacokinetically based PCA
(PKPCA), where patients can adjust target-
controlled opioid plasma concentrations seems
to be advocated only by some high-tech enthusi-
asts.37–43
Tamsen’s Prominject was the first device to
adjust background infusion rates according to
the frequency of earlier demands, but clinical
efficacy could not significantly be enhanced.44
This concept has recently caused new interest
with the introduction of “rapidly learning” PCA
devices, taking into account demand history
and electronically registered pain scores.45
Shieh et al. demonstrated for 25 extracorporeal
shock-wave lithotripsy patients that a fuzzy logic
PCA algorithm with alfentanil improved pain
relief during conscious sedation and reduced
opioid consumption. Infusion rate and bolus
size were adjusted according to a look-up table
that accepted the button-pressing history over
the last lockout intervals. Study group patients
had a mean delivery/demand ratio of 82%,
compared with 60% in conventional PCA.46
Less high-tech, but certainly useful in clinical
practice is the modification of a Graseby 3300
PCA pump, as outlined by Murray et al. The
authors changed the original handset so that
the system could be activated by mouth with
a light puff of air, which was very helpful in
rheumatoid arthritis patients who lacked the
necessary motor skills for pressing the hand
button.47 This concept has previously been re-
ported also for successful PCA in a quadri-
plegic patient.48
Elastomeric devices were more or less contin-
uously introduced since PCA received world-
wide attention. Cost considerations were not
always in favor of disposable mechanically (in
comparison with electronically) controlled
pumps, but the simple systems seem to have
found their place, particularly in ambulatory
care using local anesthetics.49,50 Banks and
Pavy reported good postoperative pain relief
after cesarean section with a pethidine-primed
disposable epidural infuser. The nursing staff
found the device easy to prime and understand,
Lehmann Vol. 29 No. 5S May 2005
the only drawback being the occasional inci-
dence of equipment failure, and patients ex-
pressed a high level of satisfaction.51 Capdevila
et al. performed a direct comparison of elec-
tronic and elastomeric PCA pumps in 76 ambu-
latory patients after orthopedic surgery who
used ropivacaine for pain control; they found
less technical problems with the disposable
devices and therefore higher patients’
acceptance.52
Newer Indications
The PCA principle was never restricted only
to intravenous opioids and postoperative pain.
Intranasal administration of lipophilic opioids
has been shown to be an effective method of
administration, which is devoid of major side
effects. Extending earlier experience with
alfentanil, butorphanol, fentanyl, oxycodone,
pethidine, or sufentanil, Ward et al. recently
investigated patient-controlled intranasal anal-
gesia (PCINA) with diamorphine (heroin) in
comparison with the intravenous route in 52
patients undergoing lower limb joint replace-
ment surgery. PCINA patients had significantly
higher VAS scores than those in the intravenous
group, both at rest and on movement. However,
significantly fewer patients in the intranasal
group suffered episodes of vomiting.53 Dale
et al. came to comparable conclusions from a
systematic review of intranasal analgesia; they
believed that nasal administration of opioids
had promising features, but was still in its in-
fancy. Improvements of nasal sprayer devices
and opioid formulations might improve clini-
cal outcome.54
PCEA was discussed at the first PCA work-
shop1 and has since then continuously been
extended into an increasing number of indica-
tions. The most recent publications deal with
labor analgesia (Petry et al. could not find a
marked advantage in adding a basal rate infu-
sion to PCEA using bupivacaine, sufentanil and
epinephrine;55 Velickovic and Leicht de-
scribed successful ropivacaine and fentanyl
PCEA in a parturient with chronic inflamma-
tory demyelinating polyneuropathy56). Patient-
controlled intrathecal analgesia, on the other
hand, is a relatively new technique. Pavy demon-
strated its successful use in two parturients
where previous back surgery made epidural an-
algesia impractical; 22 gauge spinal catheters
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
were used for the application of either bupiva-
caine and fentanyl or fentanyl, morphine, and
clonidine57, which confirmed earlier positive
experience with fentanyl or bupivacaine in or-
thopedic patients.58,59
A large number of publications indicate spe-
cial interest in the use of local anesthetics for
peripheral nerve block.60 Patient-controlled re-
gional analgesia (PCRA) has been reported for
a variety of postoperative pain situations. For
interscalene brachial plexus analgesia after
open shoulder surgery, a mixture of bupiva-
caine, sufentanil, and clonidine was most effec-
tive as a combination of continuous infusion
with PCA boluses.61 Rawal et al. found encour-
aging results with ambulatory brachial plexus
PCRA after hand surgery. Sixty patients, using
disposable elastomeric “home-pumps,” ex-
pressed high acceptance, with hardly any differ-
ences between 0.125% bupivacaine or 0.125%
ropivacaine. None of the patients showed signs
or symptoms of local anesthetic toxicity or cath-
eter infection. According to the authors, patient
selection, follow-up telephone call, and 24-hour
access to Anesthesiology services are prerequi-
sites for PCRA at home.50 Ilfeld et al. came to
comparable conclusions with 0.2% ropivacaine
using an infraclavicular brachial plexus peri-
neural catheter and a portable infusion pump
for outpatients undergoing moderately painful,
upper extremity orthopedic surgery.62 Borgeat
et al. compared interscalene PCRA with 0.2%
ropivacaine and 0.15% bupivacaine after major
open shoulder surgery. For similar pain control,
ropivacaine was associated with better pre-
servation of strength in the hand and less par-
esthesia in the fingers. Pain scores were similar
in the two groups at all times, and patient sat-
isfaction was comparable.63
Successful use of PCRA was also published for
postoperative pain relief after lower extremity
surgery. In 45 patients after total knee
arthroplasty, 0.125% bupivacaine with cloni-
dine was administered via a femoral nerve
sheath catheter either as a continuous infusion
at 10 ml/h, as a continuous infusion at 5 ml/h
plus PCRA boluses or as PCRA boluses only.
Reasonably low pain scores and supplemental
analgesia, as well as side effects and acceptance
were comparable, but bupivacaine consump-
tion was significantly less in the PCRA only
group.64 Comparable results were found in a
S77
later study with the addition of low dose sufen-
tanil to the anesthetic mixture65 and in a larger
trial with 140 patients published by Eledjam
et al., using 0.2% ropivacaine.66 Low dose epi-
nephrine did not alter the duration of 0.2%
ropivacaine PCRA in a femoral 3-in-1 block.67
Continuous subgluteus sciatic nerve blocks in
50 patients recovering from orthopedic foot
and ankle surgery were investigated by di
Benedetto et al., who used either a 10 mL/h
continuous infusion with 0.2% ropivacaine or
a 5 mL/h basal rate with 5 mL bolus every 60
minutes. The quality of pain relief and patient
acceptance was good in both groups, and none
experienced complications. Nine patients in
the continuous group versus 7 PCRA patients
required rescue morphine because of pain in
the femoral dermatomes. Ropivacaine con-
sumption was significantly less with PCRA.68
Continuous popliteal sciatic nerve block using
ropivacaine PCRA provided good pain control
and high acceptance in ambulatory patients
having moderately painful, lower extremity
orthopedic surgery, with a notable reduction of
rescue analgesics and improved quality of
sleep.69
An interesting case report by Shabat et al.
demonstrated the usefulness of PCRA for intra-
articular opioid application. A terminal 48-year-
old woman with a pathological femoral neck
fracture who was unsuitable for operative treat-
ment because of her bad general status, re-
ceived 0.25% bupivacaine as a continuous
infusion and top-up doses of 4 mg intra-articu-
lar morphine. Pain scores, maximal before be-
ginning of this treatment, were markedly
reduced, and returned to maximum after the
intra-articular catheter was removed.70 PCRA
for wound infiltration with 0.25% bupivacaine,
on the other hand, was not effective in decreas-
ing postoperative pain or opioid requirements
in a group of 50 patients undergoing major
intra-abdominal surgery.71
Patient-Controlled Sedation
Patient-controlled sedation (PCS), namely,
self-administration of sedatives and/or analge-
sics for unpleasant and painful interventions,
was suggested in the late 1980s and has since
then received considerable interest, although
there is still no review available on this topic.
S78
A list of some relevant PCS publications is in-
cluded here with limited comment; it might
not be complete. In 1988, Looper et al. first
introduced benzodiazepine self-administration
for intensive care patients for several weeks, with
daily doses of 2–4 mg midazolam.72 This concept
was later adopted, mostly with propofol, for in-
traoperative sedation in day case patients,73,74
for oral and dental75–77 or eye surgery,74,78 and
for various other surgical operations where opi-
oids were sometimes admixed or used as the
single sedative agent.79–81 Pharmacokinetically
based PCA and other dose optimization con-
cepts were often validated during PCS.46,82–84
Extracorporeal shock wave lithotripsy (ESWL)
has received special attention with the introduc-
tion of short-acting opioids such as alfentanil,
and, more recently, remifentanil.85,86
It is interesting to note that in some recent
PCS trials analgesic consumption was linked to
the painfulness of various types of surgery or the
effectiveness of surgical procedures: Tailly et al.
found that two shockwave emitters caused dif-
ferent degrees of pain during urologic ESWL,
and that analgesic consumption was higher for
kidney than for ureteral stones and highest
for stones in renal pelvis.85 Colonoscopy is gen-
erally perceived as being a painful procedure.
Contributory factors are stretching of the co-
lonic wall and mesenteric attachments from
looping of the instrument shaft, overinsuffla-
tion, the degree of torque or force applied to the
colonoscope shaft, and patient pain threshold.
Utilizing real-time magnetic endoscope im-
aging and PCS with midazolam and pethidine,
Shah et al. found that 77% of all demands oc-
curred with the colonoscope tip in the sigmoid
colon, 7% in the descending colon, 6% at the
splenic flexure, 5% in the transverse colon, and
4% in the proximal colon. Ninety percent of
all pain episodes coincided with either looping
or straightening of the colonoscope shaft, and
presumed overinsufflation was an infrequent
cause of pain (9%).87,88
Propofol and alfentanil PCS for colonoscopy
has provided a better margin of safety (lower
increase in transcutaneous pCO2 intraopera-
tively, less decrease of blood pressure postoper-
atively) than conventional premedication with
midazolam and pethidine or continuous infu-
sion, and resulted in a higher level of patient
satisfaction and shorter recovery.89 Drug con-
sumption could be further reduced and patient
Lehmann Vol. 29 No. 5S May 2005
acceptance increased in a group of 165 colonos-
copy patients whose alfentanil/propofol PCS
was combined with relaxation music.90
The ultra-short acting opioid remifentanil
is usually administered by continuous infusion
only, but intravenous PCA was reported to allow
self-controlled bolus application during labor.
Volmanen et al. found acceptable pain relief
with wide dose variations in a group of 20
healthy parturients, but maternal oxygen
desaturation, sedation, and reduced fetal heart
rate beat-to-beat variability were frequently
observed.91 Fewer side effects occurred in a
comparable study of 21 parturients without
background infusion, but again pain relief was
considered sub-optimal.92 Case reports pre-
sented by Jones et al. outlined that the patients
learned to anticipate the next contraction and
to deliver a remifentanil bolus about 30 seconds
beforehand; mothers and neonates tolerated
the opioid without sequelae.93 According to
Roelants et al., intravenous remifentanil PCA
combining low continuous background infu-
sion and small bolus doses was an alternative
in 6 women when epidural analgesia in labor
was contraindicated. Under careful anesthesia
monitoring, the technique seemed to be safe
for both mother and baby, at least when delivery
occurred at or near the normal term of
pregnancy.94
Pediatric Patient-Controlled Analgesia
The use of intravenous PCA in children has
been summed up several times in the past
years and unanimously advocated from an age
of 5–6 years onwards.95–97 This view was recently
confirmed by a newer review: The concept
continues to be developed, with PCEA, subcuta-
neous and intranasal PCA or PCS being recent
extensions of the method. When used with
adequate monitoring, PCA is a well-tolerated
technique with high patient and staff accep-
tance. It is now regarded by pediatric specialists
as a standard for the delivery of postoperative
analgesia in children aged ⬎5 years.98
Only a few original reports on pediatric PCA
have been published since 2001. Shin et al.
randomized 30 children into a conventional
intramuscular pethidine and an intravenous
nalbuphine/ketorolac PCA group. Patients
with PCA had significantly lower pain scores and
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
took less time until they were able to walk to
the bathroom, but had the same incidence of
side effects. The authors concluded that intrave-
nous PCA is safe and effective for pediatric pa-
tients who have moderate to severe pain after
operations such as rib cartilage graft, iliac bone
graft, and large flap surgeries.99 Bozkurt com-
pared the quality of analgesia and stress sup-
pression by morphine used either as single shot
by the epidural route or with intravenous PCA
in 44 children, aged 5–15 years, undergoing
major genitourinary or lower abdominal sur-
gery. Pain and sedation scores, cortisol, blood
glucose, and insulin levels were similar in
both groups, with stable hemodynamic and re-
spiratory parameters. It was therefore con-
cluded that both techniques provided sufficient
pain relief and attenuated the hormonal re-
sponse without life-threatening complica-
tions.100 Astonishingly, special preoperative
education did not improve analgesia in a group
of 93 children and adolescents, aged 8–18 years,
after spine fusion surgery. Children and par-
ents reported, however, that the standardized
educational program provided them with in-
valuable information regarding the use of PCA
and alleviated their concerns about getting
“hooked on drugs,” overdosing, side effects, and
being able to get pain relief when needed.101
A very interesting case report by Sabatowski
et al. described dramatically the use of intrave-
nous PCA in a 8-year-old boy with advanced
neuroblastoma and multiple metastases who
titrated his steadily increasing pain up to a
maximum of 2,450 mg morphine per day,
developed morphine toxicity and was then
switched to PCA with l-methadone. Within 3
days, morphine toxicity symptoms vanished
completely, and the patient used l-methadone
in doses up to 186 mg/day before he finally
died with good pain relief and without opioid-
related side effects.102
PCA in Cancer Patients
One of the major goals in the treatment of
cancer and other chronic pain situations, as
defined by the WHO ladder concept, is nonin-
vasive and anticipatory application of suitable
analgesics. PCA, typically reacting to pain in-
stead of providing prophylaxis, is therefore lim-
ited for the titration period which accompanies
S79
every WHO ladder strategy, or might be used
for the management of breakthrough pain.
Dose-finding strategies for cancer pain patients
were suggested in 1990 by Hardy and Wells,
who used the intrathecal approach,103 and from
1992 onwards by our own group for fast-track
intravenous titration of transdermal fentanyl or
slow-release morphine.104–106 This concept was
recently confirmed for the transition from in-
travenous to transdermal fentanyl by Kornick
et al. in 15 cancer patients, using a 1:1 conver-
sion ratio.107 A comparable procedure was suc-
cessful in rotation from intravenous fentanyl to
methadone PCA because of uncontrolled pain
associated with sedation or confusion. Among
the 6 patients who experienced confusion while
on fentanyl before the switch, 5 improved
within 2 days, and none showed toxicity from
methadone. The authors suggested that a con-
version ratio of 25 µg/h of fentanyl to 100 µg/h
of methadone might be safe and effective.108
It should be mentioned that the advantage
of including a fast-acting intravenous step into
the titration procedure has been questioned
several times in the past. Recently, Pearl et al.
provided evidence that early oral analgesia in
gynecologic oncology patients undergoing
intra-abdominal surgery is as safe and effica-
cious as intermediate intravenous PCA.109 On
the other hand, one must always keep in mind
that some cancer patients with a long history
of opioid use can develop serious postoperative
problems if their previous opioid consump-
tion is not taken into consideration, as demon-
strated in a case report by Heid et al., where early
PCA revealed a daily intravenous morphine
need of 600–800 mg.110
No articles have been published in the last 2
years on the use of PCA for the treatment of oral
mucositis pain, a method that is nevertheless
frequently used in many centers. Worthington
et al., in a recent systematic review, described
3 trials that compared PCA to the continuous
infusion method. Although there was no evi-
dence of a difference, less opioid was consumed
per hour for PCA. One study demonstrated that
PKPCA reduced pain compared with PCA, at the
price of higher overall opioid consumption.111
Patient-Controlled Analgesia
for Clinical Research
As in previous years, the majority of newer
PCA publications addressed clinical research
S80
topics rather than PCA itself. Space limitations
permit only a structured list of various research
topics, which the reader might nevertheless find
useful for own database searches.
Drug interactions were often investigated by
means of PCA methodology, for example, the
combination of intravenous morphine and clon-
idine;112 morphine and dextromethorphan;113
morphine and diclofenac;114 morphine and
ketamine;115,116 morphine and ketorolac;117–119
morphine, tramadol, and propacetamol;120
oxycodone and diclofenac or ketoprofen;121
tramadol, magnesium, and ketamine;122 or
tramadol and metamizol123 for postoperative pain
management. Metoclopramide reduced pain
intensity and morphine PCA consumption in
prostaglandin-induced labor for second-trimester
termination of pregnancy,124 whereas ondanse-
tron seems to inhibit tramadol efficacy.125
Intravenous PCA was used for the compari-
son of locoregional and spinal techniques, for
example, epidural analgesia with morphine
or bupivacaine, each in combination with cloni-
dine,126 spinal anesthesia with bupivacaine and
intrathecal or oral clonidine,127 intrathecal
morphine and sufentanil,128 intrathecal mor-
phine and bupivacaine,129 or spinal anesthesia
versus iliohypogastric-ilioinguinal peripheral
nerve block.130 Drug interactions during PCEA
were studied for spinal bupivacaine and fen-
tanyl,131 epidural bupivacaine or ropivacaine
alone132 or in combination with morphine,133
epidural bupivacaine or ropivacaine with sufen-
tanil,134–137 or for sufentanil dose finding for
ropivacaine supplementation.138
To investigate effective methods for reducing
postoperative nausea and vomiting during
opioid PCA, cyclizine,139 dexamethasone,140 or
ondansetron125,139,141 were tried with varying
success rates. PCA methodology was also often
used to highlight efficacy of or differences be-
tween non-PCA techniques, such as investiga-
tions into the dose-effect relationship of
parecoxib,142 the determination of equipotency
ratios between celecoxib and rofecoxib,143 or
the comparison of analgesic adenosine and
remifentanil effects.144 Relaxation and music
reduced pain after gynecologic surgery,145
whereas acupressure was ineffective with re-
spect to postoperative morphine consumption
or pain scores.146 Lumbar paravertebral nerve
block in the management of pain after total
Lehmann Vol. 29 No. 5S May 2005
hip and knee arthroplasty was not recom-
mended.147 Contrary to common expectation,
long-term advantage associated with preemp-
tive multimodal drug administration (intrave-
nous ketorolac, intra-articular morphine/
ropivacaine/epinephrine, and femoral nerve
block with ropivacaine) could not be verified in
a group of 40 outpatients undergoing anterior
cruciate ligament reconstruction.148
Of particular interest have been an in-
creasing number of surgical publications which
use PCA results as a measure to differentiate
between outcomes after various surgical tech-
niques, for example, different hernia repair
methods,149 closure or non-closure of perito-
neum at caesarean section,150 or pediatric
laparoscopic versus open splenectomy.151 Post-
operative wound oxygen tension was signifi-
cantly better with PCEA using bupivacaine and
fentanyl than with intravenous morphine PCA,
promising favorable wound healing.152 Intrave-
nous morphine/metamizol PCA convinced
orthopedic surgeons that applying a lower-than-
usual tourniquet pressure could be sufficient
for reducing postoperative pain while still pro-
viding a bloodless surgical field, and even
produce better early functional results after
total knee arthroplasty.153
Inter- and Intraindividual Variability,
Predictors of Efficacy
Current literature covering these topics in-
cludes more than 200 articles, some of which
have already been reviewed in more detail.154
Modifiers of PCA efficacy can be roughly attrib-
uted to 3 classes, but so far obviously without
unanimously accepted clinical consequences:
1. Factors related to surgery and anesthesia
• pain etiology
• overhang, antagonism, pre-emptive
analgesia
• information, acceptance by the staff
2. PCA settings
• analgesics (potency, side effects, drug
combinations)
• loading dose, demand dose, lockout
time, background infusion
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
3. Patient-related factors (kinetics and
dynamics)
• medical history
• weight, sex, age
• psychological factors (expectation, pre-
vious experience, distraction)
• ethnicity
Two recent publications addressed, more or
less directly, sex. Women after thoracotomy ex-
pressed more postoperative pain early after sur-
gery, but developed fewer complications, which
led to shorter hospitalization, in comparison
with men.17 On the other hand, women
required significantly less morphine than men
in a group of 2,298 Chinese patients.155
Chen et al. studied the reasons for patients’
wishes to continue or discontinue intravenous
PCA after a standard treatment period. Age, sex,
type of surgery, duration of PCA use, side effects,
and pain scores did not affect the decision to
continue. The reasons given by those who did
not want to restart PCA were minimal pain
(51.9%), inconvenient PCA machine (15.6%),
ineffective analgesia (11.7%), side effects
(11.7%), or wishing to tolerate pain (7.8%).
PCA morphine consumption in the 24-hour
period before cessation of PCA was larger in
patients wishing to restart PCA than in those
who did not. The authors concluded that even
cessation of PCA should be individualized.156
Pain scores are often used for adjusting PCA
dosing parameters. Bodian et al. demonstrated
that VAS scores should best be grouped into
few categories (ⱕ30, 31–70 and ⬎70) to achieve
greater clinical significance in clinical trials, and
that patients’ demands for dose corrections
were not influenced whether they saw their
earlier scores on an old form or filled in a
new one.157
As already mentioned earlier, special preop-
erative education on PCA did not improve post-
operative analgesia in children, even if they
liked the additional information.101 Compara-
ble results were also obtained from a group
of 60 women undergoing major gynecologic
surgery. Overall analgesic efficacy, side effects,
and recovery times were not affected by a struc-
tured preoperative education program. Patient
satisfaction in the education group was signifi-
cantly better than control during early recovery,
but without additional benefit in the remaining
S81
postoperative period. It was therefore con-
cluded that structured preoperative PCA educa-
tion did not affect patient outcome.158 There
is no doubt, however, that educational concepts
should and could be improved in many hospi-
tals. As outlined by Chumbley et al., patients
wished to know whether the drug used in PCA
was morphine, they wanted more information
about side effects, needed to be reassured that
PCA was safe, and that they could not overdose
or become addicted—and they wanted detailed
instructions and diagrams about the
technique!159
Cost-Benefit Considerations
One or two publications each year reflect eco-
nomic aspects of patient-controlled analgesia.
So far, no universal agreement has been
reached if costs of drugs and/or equipment,
personnel salaries, and extra time required for
servicing devices or special monitoring match
the outcome, which could be measured by
fewer complications, reduced hospitalization
time, or less chronification, or just by patients’
satisfaction (and their recommendation rate
for this particular hospital).160–167 As has been
shown in this update, PCA cannot be consid-
ered an entity by itself—there are just too many
modifications in use, too many application
modes combined with too many drug interac-
tions, and so forth, which all influence efficacy
in an individual setting. Patients are obviously
aware that good care has its price, and they seem
willing to pay for it.168 Most specialist nowadays
agree that whatever methodology is used,
results are best when organization is optimal,
which requires a well-trained team of nurses and
physicians167,169 and adequate education.170
This background must always be kept in mind
when newer results are discussed, and it might
explain why common consensus is still far away.
Length of hospitalization and direct medical
costs for patients recovering from surgery of
the abdominal aorta were comparable between
intravenous and epidural PCA.25 Comparable
satisfaction and hospital discharge time were
achieved for PCEA versus intrathecal mor-
phine after cesarean section, and even if man-
power and drug costs were equal in both
groups, the difference in total costs amounted
to 33 Euros (about US$ 29) and was mainly
S82
caused by the more expensive equipment
required for PCEA.31 The combination of intra-
venous PCA with continuous epidural analge-
sia produced better pain relief than PCA
alone, reduced postoperative complications,
and allowed faster recovering activities of daily
life. However, the length of hospital stay and
medical expense were not significantly
different.171
Knight et al. compared standard and fast-
track care pathways in 60 patients undergoing
open donor nephrectomy who received, by sur-
geon preference, either ketorolac only, ketoro-
lac plus spinal morphine, or intravenous opioid
PCA. Median hospital stay was 2 days for the
two fast-track ketorolac pathways compared to
3 days for PCA. Delayed oral intake was seen
in 3–6% of patients on ketorolac, but in 83%
with PCA. Although resumption of daily activi-
ties was comparable, the authors calculated a
significant difference in mean global cost
($9,394 for the ketorolac only group, $9,238 for
ketorolac plus spinal morphine, and $11,601
for PCA).172
Safety Aspects and Mishaps
On the whole, PCA appears to be safe and
can probably help reduce typical postoperative
complications.2 Most communications covering
the safety aspect are more or less anecdotal,
and it must be assumed that some mishaps hap-
pened without proper publication.
Simopoulos et al. concluded, from a retro-
spective analysis of 355 medical records, that
norpethidine central nervous toxicity was best
prevented by reducing daily intravenous pethi-
dine PCA doses to 10 mg/kg for not longer
than 3 days, if renal dysfunction or enhanced
hepatic metabolism of pethidine were ex-
cluded.173 Chan et al. did not find a correlation
between intravenous PCA morphine dose and
the time of first passage of flatus in 51 women
and suggested that the favorable pharmacoki-
netic profile of PCA could help reduce the
morphine-induced bowel dysfunction at its
therapeutic level.174 In a study of 459 parturi-
ents, epidural analgesia with 0.0625% bupiva-
caine and fentanyl prolonged the active phase
of labor by 1 hour compared with intravenous
pethidine PCA. The rate of cervical dilation
was significantly less with epidural analgesia,
Lehmann Vol. 29 No. 5S May 2005
and also the duration of the second stage
tended to be longer175—not an uncommon
observation with epidural techniques.176 In an
earlier study the same group of authors did not
find any indication for higher cesarean section
rates in a group of 715 patients receiving either
PCEA with bupivacaine and fentanyl or intrave-
nous pethidine PCA.177
PCEA using 0.1% bupivacaine with fentanyl
produced adequate analgesia on the first post-
operative day after general, orthopedic, gyneco-
logic, and plastic surgery in 92.5% of 1,057
patients, of whom 96.2% were free of nausea.
During a total of 3,858 treatment days, two
patients (0.19%) had an episode of severe respi-
ratory depression and one patient (0.09%)
became unarousable. Hypotension occurred in
45 patients (4.3%). There were no cases of
epidural hematoma or abscess. From these re-
sults, Wigfull and Welchew concluded that
PCEA was both efficacious and safe on surgi-
cal wards.178
Although most PCA devices on today’s
market were classified technically acceptable
with respect to safety,179,180 mishaps from tech-
nical problems continue to happen. Most ear-
lier reported incidents were associated with
respiratory depression,181–183 sometimes caused
by ignoring the correlation between opioid
dose, analgesia, sedation, and the resulting de-
pression of the brainstem reticular formation.
This series was prolonged in the last years by
three short communications about faulty de-
vices or programming errors, some unfortu-
nately with fatal outcomes,184–186 stressing once
more the long ago published recommendations
to avoid PCA mishaps by proper selection of
patients, adequate monitoring, and thorough
education of the staff involved.187
Conclusion
The concept of patient-controlled analgesia
was one of the most important developments
in pain management, not simply because it pro-
vided better analgesia to patients but also be-
cause it improved our understanding of pain
and suffering, and because it forced medical
care providers to no longer close their eyes.
There might be more effective strategies for
acute and chronic pain relief than intravenous
opioids, but even this insight was strongly
Vol. 29 No. 5S May 2005 Developments in Patient-Controlled Analgesia
supported by the “incredible” results which
continue to be produced in ever increasing
numbers.
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