Lehmann 2005

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

the very large variability of the responses of
Twenty years ago, in June 1984, a small group
of enthusiasts met in Leeds Castle, UK, for the patients, and are all dependent upon the inter-
first International Workshop on Patient-Con- pretation of nurses of prescriptions by physi-
trolled Analgesia.1 We were convinced “that the cians.” Among the topics we discussed at that
present methods of routinely prescribing a vari- time were the use of patient-controlled analge-
ety of analgesic drugs given either intramuscu- sia (PCA) for research (analgesic drugs and
larly or subcutaneously, and occasionally by analgesia, variability in patient characteristics,
mouth if the surgical conditions permits, were pharmacokinetics and pharmacodynamics, bio-
not satisfactory in controlling pain and provid- feedback systems), as well as early clinical expe-
ing comfort for postoperative patients,” be- rience with application strategies, routes of
administration, and various opioids. None of us
expected PCA to become the gold standard of
Address reprint requests to: Klaus A. Lehmann, MD,
acute pain management, or—even more im-
PhD, Department of Anesthesiology, University of portant—to change our understanding of pain
Cologne, Joseph-Stelzmann-Strasse 9, D-50924 Köln, and suffering. PCA later influenced the concept
Germany. of acute pain services; the introduction of
Accepted for publication: January 5, 2005. 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 S73
regional anesthesia, and labor; and the develop- devices available can apply the WYNIWYG strat-
ment of treatments for children, cancer pa- egy. This involves trusting the patient, providing
tients, and chronic pain patients. Up to now, adequate monitoring and appropriate docu-
more than 1,700 papers have been published mentation, and, of course, raising the educa-
on the use of PCA, including nearly 200 reviews tional level of the staff on surgical wards.
and three meta-analyses.2–4
This update will primarily discuss the most
recent developments in postoperative pain and
Efficacy of PCA in Comparison
highlight the variability of drug use patterns in with Other Pain Relieving Techniques
PCA for acute and cancer pain. It will Walder et al., in a recent meta-analysis, ana-
concentrate on articles published since 2001. lyzed 32 trials in which morphine, pethidine
Space restriction prevents in-depth discussion (meperidine), piritramide, nalbuphine, or tra-
of methodology or quality of results (readers madol had been administered either by PCA
are referred to newer reviews on safety and effi- or intramuscularly, intravenously, or subcutane-
cacy5,6 or drug interactions7). The author’s ously. The evidence shows that, in the post-
main interest is to outline the shift from early operative setting, opioid PCA, compared with
expectation to today’s routine. This includes conventional opioid treatment, improves anal-
the discussion of patients’ attitudes towards gesia and decreases the risk of pulmonary com-
PCA, its efficacy and safety compared with other plications. Patients prefer PCA.2
strategies, and newer application modes and Dolin et al. collected pooled postoperative
indications. 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-
PCA Principle and the WYNIWYG ponding values were 35.8% and 10.4% for PCA,
Concept and 20.9% and 7.8% for epidural analgesia,
The name of the game is individual variabil- respectively.3
ity.8 PCA deals with this problem by allowing Comparing epidural infusion or continuous
individual titration. Analgesic consumption femoral block with local anesthetics and intrave-
may be huge, with an average much higher nous morphine PCA in 56 patients, Capdevila
than earlier thought possible. Patients’ accep- et al. found significantly lower pain scores at
tance is overwhelming, because they no longer rest and during passive motion for both re-
have to wait for compassionate nurses or doc- gional anesthesia groups. Early postoperative
tors to provide analgesia (although the impor- knee mobilization following epidural infusion
tance of self-control has been questioned and femoral block was significantly better
recently9), and the staff can learn from patients than with PCA, and average durations of stay
how to individualize analgesic needs. The in- in the rehabilitation center significantly
sight that thresholds are unpredictable in indi- shorter: 37–40 days after epidural or femoral
vidual patients (both subjective and objective block compared with 50 days in the morphine
parameters such as plasma concentrations) is PCA group. Side effects, however, were encoun-
one of the greatest merits of PCA. Any tech- tered more frequently with epidural infusion.10
nique based on this knowledge and committed Similar results were obtained by Chelley et al.
to immediate reaction (the “PCA principle”) with 92 arthroplasty patients, where 3-in-1 and
can in theory be considered equivalent. It sciatic blocks followed by femoral infusion with
became more and more evident that different local anesthetics significantly reduced post-
PCA modes (by any route or device) are not operative morphine requirement by 74% com-
universally superior to nurse-controlled tech- pared with intravenous PCA, and by 35%
niques. Low-cost techniques based on the compared with epidural analgesia. The blocks
“WYNIWYG (what you need is what you get) also provided better recovery, were associated
concept” have been shown to be equally effec- with reduced postoperative bleeding and al-
tive. In my opinion, PCA was of utmost impor- lowed better performance on continuous pas-
tance until the PCA principle was discovered. sive motion, which led to a 20% decrease in the
Even those who have no (or not enough) PCA length of hospitalization.11
S74 Lehmann Vol. 29 No. 5S May 2005
Direct continuous local wound perfusion of et al., on the other hand, did not find any differ-
0.5% bupivacaine for 60 hours was as effective as ence in the incidence of long-term chronic pain
intravenous morphine PCA for postoperative after thoracotomy, with either intraoperative
pain relief in 70 patients after laparotomy for epidural bupivacaine and fentanyl or placebo,
major colorectal surgery, with no significant dif- although early analgesic consumption was
ference in pain scores at rest and movement, significantly reduced in the former group.17
except for pain at rest on the first postoperative Pulmonary outcomes was not influenced in
day, when PCA scored slightly better.12 In a 54 patients with lung cancer undergoing thora-
group of 114 patients undergoing gastric bypass cotomy who received postoperatively con-
surgery as a treatment for obesity, the combina- tinuous epidural infusion (ropivacaine with
tion of effective preincision local anesthetic in- sufentanil) or intravenous morphine PCA.
filtration, preextubation supplemental field Both techniques provided good analgesia at
infiltration (each with bupivacaine) and post- rest, but PCA was less effective during mobiliza-
tion. Postoperative respiratory function and ar-
operative intravenous morphine PCA produced
terial blood gas values were reduced compared
lower pain scores than thoracic epidural analge-
with preoperative values, but without significant
sia with bupivacaine and pethidine or intra-
differences between groups at any time, and CT
venous morphine PCA without pretreatment.13
scans revealed comparable amounts of atelecta-
In another trial, patient-controlled epidural an-
sis.18 Efficacy of intravenous morphine PCA
esthesia (PCEA) with bupivacaine and fentanyl after thoracotomy could be significantly in-
provided better pain relief than continuous creased by presurgical lumbar intrathecal
intra-articular local anesthetic infusion in 168 injection of 0.5 mg morphine and/or 50 µg
patients recovering from knee surgery.14 sufentanil.19
More and more studies do not only address When compared with continuous postopera-
postoperative pain intensity but also the influ- tive, intravenous pain therapy or PCA, intra- and
ence that pain might have on recovery and/ postoperative thoracic epidural anesthesia
or chronification. Results are often conflicting, using bupivacaine and fentanyl significantly re-
but most investigations show a trend for better duced the length of stay in the intensive care
outcome when spinal application is used in- unit, the administration of antibiotics, days
stead of intravenous routes, and that local anes- without oral nutrition, and the rate of anasto-
thetics are more effective than opioids. One mosis insufficiencies in a group of 175 patients
possible reason why improved outcome is often with gastrointestinal carcinoma. Epidural an-
so difficult to demonstrate is that pain manage- esthesia also led to less frequent vomiting and
ment strategies are not yet sufficiently in- earlier resumption of gastrointestinal motility.
tegrated with overall perioperative care and However, these positive effects did not have
postoperative rehabilitation.15 a significant beneficial impact on overall
Sentürk et al. found a 62% incidence of hospitalization.20
chronic pain after thoracotomy, with an in- Carli et al. randomized 64 patients under-
crease to 83% in patients who experienced going elective colonic resection to either intra-
pain on the second postoperative day. In their venous morphine PCA or thoracic epidural
69 patients, pain was better controlled by tho- analgesia with bupivacaine and fentanyl. The
superior quality of pain relief provided by epi-
racic epidural analgesia with preoperative initi-
dural analgesia had a positive impact on out-
ation (using bupivacaine and morphine),
of-bed mobilization, bowel function, and intake
followed by postoperative PCEA with the same
of food, with long-lasting effects on exercise ca-
drug combination, than by intravenous mor- pacity and health-related quality of life. Length
phine PCA alone. The authors concluded that of hospital stay and incidence of complications
preoperatively initiated thoracic epidural anal- were similar in both groups, although patients in
gesia had the most satisfying results in con- the epidural group were ready to be discharged
trolling postthoracotomy pain in the acute and earlier.21 These results are in accordance with
long-term period, and that it was associated a previous report on 42 patients by the same
with a decreased incidence (and intensity) of group.22 Paulsen et al., on the other hand, con-
chronic pain compared with postoperative (epi- firmed superior pain control with thoracic epi-
dural or intravenous) analgesia.16 Ochroch dural analgesia (bupivacaine/fentanyl), but did
not find significant advantages over intravenous with 240 obstetric patients, where both intrave-
morphine or pethidine PCA with respect to nous and epidural PCA had excellent analgesic
return of bowel function in 49 patients after effect. Urinary retention was less and sedation
bowel resection, again with no difference in higher with intravenous PCA, and recovery of
discharge times. This might have been caused bowel movement faster with PCEA.28
by a higher incidence of complications (fever, Multimodal analgesia (a combination of epi-
urinary retention, urinary tract or wound infec- dural opioid/local anesthetic and systemic ket-
tion, and oversedation) in the epidural group orolac for 48 hours) allowed significantly better
(61% vs. 29%).23 Quality of analgesia, particu- pain control at rest and coughing, compared
larly on coughing, and sleep could be signifi- with intravenous fentanyl or morphine PCA in
cantly improved in gastrectomy patients who 47 intravenous nutrition patients recovering
had thoracic PCEA (bupivacaine and fentanyl) from major upper abdominal surgery. Only the
supplemented by slow continuous infusion multimodal analgesia group maintained total
during the nights.24 body protein and fat. Nitrogen balance and the
In 168 patients undergoing surgery of the hormonal response to surgery were not consis-
abdominal aorta, thoracic epidural anesthesia tently influenced by the treatment modality.29
combined with light general anesthesia and fol- In a systematic review of 9 studies (including
lowed by either intravenous or epidural PCA 640 patients) to compare efficacy and safety of
offered no major advantage or disadvantage PCEA and continuous epidural labor anesthesia
when compared with general anesthesia with local anesthetics, van der Vyver et al. con-
alone followed by either intravenous or epi- cluded that fewer anesthetic interventions were
dural PCA. Although PCEA was associated with necessary for PCEA, which also received less
a significantly shorter time to extubation, post- local anesthetic and therefore developed less
operative pain scores and outcomes were simi- motor block. Both methods were safe for mother
lar among the four treatment groups with and newborn.4 When local anesthetics were
compared with opioids in women with severe
respect to death, myocardial infarction, myocar-
eclampsia, epidural analgesia using bupiva-
dial ischemia, reoperation, pneumonia, and
caine and fentanyl provided significantly better
renal failure. Length of hospitalization and
pain relief than intravenous pethidine PCA. Pa-
direct medical costs for patients surviving to
tients who received epidural analgesia needed
discharge were also comparable.25
ephedrine more often for the treatment of hy-
Intra- and postoperative thoracic epidural an-
potension, but their infants were less likely to
algesia (ropivacaine and morphine) compared
need naloxone at delivery (9% vs. 54%). Com-
with intravenous morphine PCA offered signifi-
pared with intravenous opioid PCA, intrapar-
cantly improved pain control after breast recon-
tum epidural analgesia did not significantly
struction in 18 patients investigated by Correll
increase the cesarean delivery rate.30 Epidural
et al. Time to first ambulation, to first bowel PCA after cesarean section with a mixture of
sounds, to tolerating oral nutrition, incidence 0.06% bupivacaine and sufentanil was more
of nausea/vomiting or pruritus, and time to first effective than intrathecal 0.15 mg morphine and
flatus were not statistically different between the paracetamol/tramadol supplementation.31
groups, but the epidural technique resulted in
a 25-hour reduction in time of hospitalization.26
Chen et al. performed a direct comparison New Devices and Application
of epidural and intravenous pethidine PCA in 37 Strategies
patients after total gastrectomy. Pain scores, Optimal application modes for PCA were
side effects (nausea, vomiting, pruritus, and discussed from the very beginning. Over the
sedation), patient satisfaction, and length of years, it became evident that continuous, that
hospital stay were similar between the groups. is, demand-independent background infusions
Mean cumulative pethidine consumption in the usually did not improve the quality of analgesia
first 24 hours was 33% less in the epidural than but increased overall opioid consumption with
in the intravenous group, although most of this the risk of higher incidences of respiratory de-
difference occurred in the first 8 postoperative pression32—a result which was recently re-
hours.27 Similar results were found in a study confirmed in a study with nalbuphine PCA.33
“Best” demand doses seem to exist for each the only drawback being the occasional inci-
opioid with respect to immediate onset of dence of equipment failure, and patients ex-
action, efficacy, and control of side effects.34 pressed a high level of satisfaction.51 Capdevila
Variable dose PCA, as recommended by Owen et al. performed a direct comparison of elec-
et al.,35,36 where patients have the choice be- tronic and elastomeric PCA pumps in 76 ambu-
tween three demand buttons delivering 0.5–1.5 latory patients after orthopedic surgery who
mg of morphine, are obviously only seldom used. used ropivacaine for pain control; they found
The concept of pharmacokinetically based PCA less technical problems with the disposable
(PKPCA), where patients can adjust target- devices and therefore higher patients’
controlled opioid plasma concentrations seems acceptance.52
to be advocated only by some high-tech enthusi-
asts.37–43
Tamsen’s Prominject was the first device to Newer Indications
adjust background infusion rates according to The PCA principle was never restricted only
the frequency of earlier demands, but clinical to intravenous opioids and postoperative pain.
efficacy could not significantly be enhanced.44 Intranasal administration of lipophilic opioids
This concept has recently caused new interest has been shown to be an effective method of
with the introduction of “rapidly learning” PCA administration, which is devoid of major side
devices, taking into account demand history effects. Extending earlier experience with
and electronically registered pain scores.45 alfentanil, butorphanol, fentanyl, oxycodone,
Shieh et al. demonstrated for 25 extracorporeal pethidine, or sufentanil, Ward et al. recently
shock-wave lithotripsy patients that a fuzzy logic investigated patient-controlled intranasal anal-
PCA algorithm with alfentanil improved pain gesia (PCINA) with diamorphine (heroin) in
relief during conscious sedation and reduced comparison with the intravenous route in 52
opioid consumption. Infusion rate and bolus patients undergoing lower limb joint replace-
size were adjusted according to a look-up table ment surgery. PCINA patients had significantly
that accepted the button-pressing history over higher VAS scores than those in the intravenous
the last lockout intervals. Study group patients group, both at rest and on movement. However,
had a mean delivery/demand ratio of 82%, significantly fewer patients in the intranasal
compared with 60% in conventional PCA.46 group suffered episodes of vomiting.53 Dale
Less high-tech, but certainly useful in clinical et al. came to comparable conclusions from a
practice is the modification of a Graseby 3300 systematic review of intranasal analgesia; they
PCA pump, as outlined by Murray et al. The believed that nasal administration of opioids
authors changed the original handset so that had promising features, but was still in its in-
the system could be activated by mouth with fancy. Improvements of nasal sprayer devices
a light puff of air, which was very helpful in and opioid formulations might improve clini-
rheumatoid arthritis patients who lacked the cal outcome.54
necessary motor skills for pressing the hand PCEA was discussed at the first PCA work-
button.47 This concept has previously been re- shop1 and has since then continuously been
ported also for successful PCA in a quadri- extended into an increasing number of indica-
plegic patient.48 tions. The most recent publications deal with
Elastomeric devices were more or less contin- labor analgesia (Petry et al. could not find a
uously introduced since PCA received world- marked advantage in adding a basal rate infu-
wide attention. Cost considerations were not sion to PCEA using bupivacaine, sufentanil and
always in favor of disposable mechanically (in epinephrine;55 Velickovic and Leicht de-
comparison with electronically) controlled scribed successful ropivacaine and fentanyl
pumps, but the simple systems seem to have PCEA in a parturient with chronic inflamma-
found their place, particularly in ambulatory tory demyelinating polyneuropathy56). Patient-
care using local anesthetics.49,50 Banks and controlled intrathecal analgesia, on the other
Pavy reported good postoperative pain relief hand, is a relatively new technique. Pavy demon-
after cesarean section with a pethidine-primed strated its successful use in two parturients
disposable epidural infuser. The nursing staff where previous back surgery made epidural an-
found the device easy to prime and understand, algesia impractical; 22 gauge spinal catheters
were used for the application of either bupiva- later study with the addition of low dose sufen-
caine and fentanyl or fentanyl, morphine, and tanil to the anesthetic mixture65 and in a larger
clonidine57, which confirmed earlier positive trial with 140 patients published by Eledjam
experience with fentanyl or bupivacaine in or- et al., using 0.2% ropivacaine.66 Low dose epi-
thopedic patients.58,59 nephrine did not alter the duration of 0.2%
A large number of publications indicate spe- ropivacaine PCRA in a femoral 3-in-1 block.67
cial interest in the use of local anesthetics for Continuous subgluteus sciatic nerve blocks in
peripheral nerve block.60 Patient-controlled re- 50 patients recovering from orthopedic foot
gional analgesia (PCRA) has been reported for and ankle surgery were investigated by di
a variety of postoperative pain situations. For Benedetto et al., who used either a 10 mL/h
interscalene brachial plexus analgesia after continuous infusion with 0.2% ropivacaine or
open shoulder surgery, a mixture of bupiva- a 5 mL/h basal rate with 5 mL bolus every 60
caine, sufentanil, and clonidine was most effec- minutes. The quality of pain relief and patient
tive as a combination of continuous infusion acceptance was good in both groups, and none
with PCA boluses.61 Rawal et al. found encour- experienced complications. Nine patients in
aging results with ambulatory brachial plexus the continuous group versus 7 PCRA patients
PCRA after hand surgery. Sixty patients, using required rescue morphine because of pain in
disposable elastomeric “home-pumps,” ex- the femoral dermatomes. Ropivacaine con-
pressed high acceptance, with hardly any differ- sumption was significantly less with PCRA.68
ences between 0.125% bupivacaine or 0.125% Continuous popliteal sciatic nerve block using
ropivacaine. None of the patients showed signs ropivacaine PCRA provided good pain control
or symptoms of local anesthetic toxicity or cath- and high acceptance in ambulatory patients
eter infection. According to the authors, patient having moderately painful, lower extremity
selection, follow-up telephone call, and 24-hour orthopedic surgery, with a notable reduction of
access to Anesthesiology services are prerequi- rescue analgesics and improved quality of
sleep.69
sites for PCRA at home.50 Ilfeld et al. came to
An interesting case report by Shabat et al.
comparable conclusions with 0.2% ropivacaine
demonstrated the usefulness of PCRA for intra-
using an infraclavicular brachial plexus peri-
articular opioid application. A terminal 48-year-
neural catheter and a portable infusion pump
old woman with a pathological femoral neck
for outpatients undergoing moderately painful,
fracture who was unsuitable for operative treat-
upper extremity orthopedic surgery.62 Borgeat
ment because of her bad general status, re-
et al. compared interscalene PCRA with 0.2%
ceived 0.25% bupivacaine as a continuous
ropivacaine and 0.15% bupivacaine after major
infusion and top-up doses of 4 mg intra-articu-
open shoulder surgery. For similar pain control,
lar morphine. Pain scores, maximal before be-
ropivacaine was associated with better pre-
ginning of this treatment, were markedly
servation of strength in the hand and less par- reduced, and returned to maximum after the
esthesia in the fingers. Pain scores were similar intra-articular catheter was removed.70 PCRA
in the two groups at all times, and patient sat- for wound infiltration with 0.25% bupivacaine,
isfaction was comparable.63 on the other hand, was not effective in decreas-
Successful use of PCRA was also published for ing postoperative pain or opioid requirements
postoperative pain relief after lower extremity in a group of 50 patients undergoing major
surgery. In 45 patients after total knee intra-abdominal surgery.71
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 Patient-Controlled Sedation
plus PCRA boluses or as PCRA boluses only. Patient-controlled sedation (PCS), namely,
Reasonably low pain scores and supplemental self-administration of sedatives and/or analge-
analgesia, as well as side effects and acceptance sics for unpleasant and painful interventions,
were comparable, but bupivacaine consump- was suggested in the late 1980s and has since
tion was significantly less in the PCRA only then received considerable interest, although
group.64 Comparable results were found in a there is still no review available on this topic.
A list of some relevant PCS publications is in- acceptance increased in a group of 165 colonos-
cluded here with limited comment; it might copy patients whose alfentanil/propofol PCS
not be complete. In 1988, Looper et al. first was combined with relaxation music.90
introduced benzodiazepine self-administration The ultra-short acting opioid remifentanil
for intensive care patients for several weeks, with is usually administered by continuous infusion
daily doses of 2–4 mg midazolam.72 This concept only, but intravenous PCA was reported to allow
was later adopted, mostly with propofol, for in- self-controlled bolus application during labor.
traoperative sedation in day case patients,73,74 Volmanen et al. found acceptable pain relief
for oral and dental75–77 or eye surgery,74,78 and with wide dose variations in a group of 20
for various other surgical operations where opi- healthy parturients, but maternal oxygen
oids were sometimes admixed or used as the desaturation, sedation, and reduced fetal heart
single sedative agent.79–81 Pharmacokinetically rate beat-to-beat variability were frequently
based PCA and other dose optimization con- observed.91 Fewer side effects occurred in a
cepts were often validated during PCS.46,82–84 comparable study of 21 parturients without
Extracorporeal shock wave lithotripsy (ESWL) background infusion, but again pain relief was
has received special attention with the introduc- considered sub-optimal.92 Case reports pre-
tion of short-acting opioids such as alfentanil, sented by Jones et al. outlined that the patients
and, more recently, remifentanil.85,86 learned to anticipate the next contraction and
It is interesting to note that in some recent to deliver a remifentanil bolus about 30 seconds
PCS trials analgesic consumption was linked to beforehand; mothers and neonates tolerated
the painfulness of various types of surgery or the the opioid without sequelae.93 According to
effectiveness of surgical procedures: Tailly et al. Roelants et al., intravenous remifentanil PCA
found that two shockwave emitters caused dif- combining low continuous background infu-
ferent degrees of pain during urologic ESWL, sion and small bolus doses was an alternative
and that analgesic consumption was higher for in 6 women when epidural analgesia in labor
kidney than for ureteral stones and highest was contraindicated. Under careful anesthesia
for stones in renal pelvis.85 Colonoscopy is gen- monitoring, the technique seemed to be safe
erally perceived as being a painful procedure. for both mother and baby, at least when delivery
Contributory factors are stretching of the co- occurred at or near the normal term of
lonic wall and mesenteric attachments from pregnancy.94
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- Pediatric Patient-Controlled Analgesia
aging and PCS with midazolam and pethidine, The use of intravenous PCA in children has
Shah et al. found that 77% of all demands oc- been summed up several times in the past
curred with the colonoscope tip in the sigmoid years and unanimously advocated from an age
colon, 7% in the descending colon, 6% at the of 5–6 years onwards.95–97 This view was recently
splenic flexure, 5% in the transverse colon, and confirmed by a newer review: The concept
4% in the proximal colon. Ninety percent of continues to be developed, with PCEA, subcuta-
all pain episodes coincided with either looping neous and intranasal PCA or PCS being recent
or straightening of the colonoscope shaft, and extensions of the method. When used with
presumed overinsufflation was an infrequent adequate monitoring, PCA is a well-tolerated
cause of pain (9%).87,88 technique with high patient and staff accep-
Propofol and alfentanil PCS for colonoscopy tance. It is now regarded by pediatric specialists
has provided a better margin of safety (lower as a standard for the delivery of postoperative
increase in transcutaneous pCO2 intraopera- analgesia in children aged ⬎5 years.98
tively, less decrease of blood pressure postoper- Only a few original reports on pediatric PCA
atively) than conventional premedication with have been published since 2001. Shin et al.
midazolam and pethidine or continuous infu- randomized 30 children into a conventional
sion, and resulted in a higher level of patient intramuscular pethidine and an intravenous
satisfaction and shorter recovery.89 Drug con- nalbuphine/ketorolac PCA group. Patients
sumption could be further reduced and patient with PCA had significantly lower pain scores and
took less time until they were able to walk to every WHO ladder strategy, or might be used
the bathroom, but had the same incidence of for the management of breakthrough pain.
side effects. The authors concluded that intrave- Dose-finding strategies for cancer pain patients
nous PCA is safe and effective for pediatric pa- were suggested in 1990 by Hardy and Wells,
tients who have moderate to severe pain after who used the intrathecal approach,103 and from
operations such as rib cartilage graft, iliac bone 1992 onwards by our own group for fast-track
graft, and large flap surgeries.99 Bozkurt com- intravenous titration of transdermal fentanyl or
pared the quality of analgesia and stress sup- slow-release morphine.104–106 This concept was
pression by morphine used either as single shot recently confirmed for the transition from in-
by the epidural route or with intravenous PCA travenous to transdermal fentanyl by Kornick
in 44 children, aged 5–15 years, undergoing et al. in 15 cancer patients, using a 1:1 conver-
major genitourinary or lower abdominal sur- sion ratio.107 A comparable procedure was suc-
gery. Pain and sedation scores, cortisol, blood cessful in rotation from intravenous fentanyl to
glucose, and insulin levels were similar in methadone PCA because of uncontrolled pain
both groups, with stable hemodynamic and re- associated with sedation or confusion. Among
spiratory parameters. It was therefore con- the 6 patients who experienced confusion while
cluded that both techniques provided sufficient on fentanyl before the switch, 5 improved
pain relief and attenuated the hormonal re- within 2 days, and none showed toxicity from
sponse without life-threatening complica- methadone. The authors suggested that a con-
tions.100 Astonishingly, special preoperative version ratio of 25 µg/h of fentanyl to 100 µg/h
education did not improve analgesia in a group of methadone might be safe and effective.108
of 93 children and adolescents, aged 8–18 years, It should be mentioned that the advantage
after spine fusion surgery. Children and par- of including a fast-acting intravenous step into
ents reported, however, that the standardized the titration procedure has been questioned
educational program provided them with in- several times in the past. Recently, Pearl et al.
valuable information regarding the use of PCA provided evidence that early oral analgesia in
gynecologic oncology patients undergoing
and alleviated their concerns about getting
intra-abdominal surgery is as safe and effica-
“hooked on drugs,” overdosing, side effects, and
cious as intermediate intravenous PCA.109 On
being able to get pain relief when needed.101
the other hand, one must always keep in mind
A very interesting case report by Sabatowski
that some cancer patients with a long history
et al. described dramatically the use of intrave-
of opioid use can develop serious postoperative
nous PCA in a 8-year-old boy with advanced
problems if their previous opioid consump-
neuroblastoma and multiple metastases who tion is not taken into consideration, as demon-
titrated his steadily increasing pain up to a strated in a case report by Heid et al., where early
maximum of 2,450 mg morphine per day, PCA revealed a daily intravenous morphine
developed morphine toxicity and was then need of 600–800 mg.110
switched to PCA with l-methadone. Within 3 No articles have been published in the last 2
days, morphine toxicity symptoms vanished years on the use of PCA for the treatment of oral
completely, and the patient used l-methadone mucositis pain, a method that is nevertheless
in doses up to 186 mg/day before he finally frequently used in many centers. Worthington
died with good pain relief and without opioid- et al., in a recent systematic review, described
related side effects.102 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
PCA in Cancer Patients PKPCA reduced pain compared with PCA, at the
One of the major goals in the treatment of price of higher overall opioid consumption.111
cancer and other chronic pain situations, as
defined by the WHO ladder concept, is nonin-
vasive and anticipatory application of suitable
Patient-Controlled Analgesia
analgesics. PCA, typically reacting to pain in- for Clinical Research
stead of providing prophylaxis, is therefore lim- As in previous years, the majority of newer
ited for the titration period which accompanies PCA publications addressed clinical research
topics rather than PCA itself. Space limitations hip and knee arthroplasty was not recom-
permit only a structured list of various research mended.147 Contrary to common expectation,
topics, which the reader might nevertheless find long-term advantage associated with preemp-
useful for own database searches. tive multimodal drug administration (intrave-
Drug interactions were often investigated by nous ketorolac, intra-articular morphine/
means of PCA methodology, for example, the ropivacaine/epinephrine, and femoral nerve
combination of intravenous morphine and clon- block with ropivacaine) could not be verified in
idine;112 morphine and dextromethorphan;113 a group of 40 outpatients undergoing anterior
morphine and diclofenac;114 morphine and cruciate ligament reconstruction.148
ketamine;115,116 morphine and ketorolac;117–119 Of particular interest have been an in-
morphine, tramadol, and propacetamol;120 creasing number of surgical publications which
oxycodone and diclofenac or ketoprofen;121 use PCA results as a measure to differentiate
tramadol, magnesium, and ketamine;122 or between outcomes after various surgical tech-
tramadol and metamizol123 for postoperative pain niques, for example, different hernia repair
management. Metoclopramide reduced pain methods,149 closure or non-closure of perito-
intensity and morphine PCA consumption in neum at caesarean section,150 or pediatric
prostaglandin-induced labor for second-trimester laparoscopic versus open splenectomy.151 Post-
termination of pregnancy,124 whereas ondanse- operative wound oxygen tension was signifi-
tron seems to inhibit tramadol efficacy.125 cantly better with PCEA using bupivacaine and
Intravenous PCA was used for the compari- fentanyl than with intravenous morphine PCA,
son of locoregional and spinal techniques, for promising favorable wound healing.152 Intrave-
example, epidural analgesia with morphine nous morphine/metamizol PCA convinced
or bupivacaine, each in combination with cloni- orthopedic surgeons that applying a lower-than-
dine,126 spinal anesthesia with bupivacaine and usual tourniquet pressure could be sufficient
intrathecal or oral clonidine,127 intrathecal for reducing postoperative pain while still pro-
viding a bloodless surgical field, and even
morphine and sufentanil,128 intrathecal mor-
produce better early functional results after
phine and bupivacaine,129 or spinal anesthesia
total knee arthroplasty.153
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- Inter- and Intraindividual Variability,
tanil,134–137 or for sufentanil dose finding for Predictors of Efficacy
ropivacaine supplementation.138 Current literature covering these topics in-
To investigate effective methods for reducing cludes more than 200 articles, some of which
postoperative nausea and vomiting during have already been reviewed in more detail.154
opioid PCA, cyclizine,139 dexamethasone,140 or Modifiers of PCA efficacy can be roughly attrib-
ondansetron125,139,141 were tried with varying uted to 3 classes, but so far obviously without
success rates. PCA methodology was also often unanimously accepted clinical consequences:
used to highlight efficacy of or differences be-
tween non-PCA techniques, such as investiga- 1. Factors related to surgery and anesthesia
tions into the dose-effect relationship of • pain etiology
parecoxib,142 the determination of equipotency • overhang, antagonism, pre-emptive
ratios between celecoxib and rofecoxib,143 or analgesia
the comparison of analgesic adenosine and • information, acceptance by the staff
remifentanil effects.144 Relaxation and music
2. PCA settings
reduced pain after gynecologic surgery,145
whereas acupressure was ineffective with re- • analgesics (potency, side effects, drug
spect to postoperative morphine consumption combinations)
or pain scores.146 Lumbar paravertebral nerve • loading dose, demand dose, lockout
block in the management of pain after total time, background infusion
3. Patient-related factors (kinetics and postoperative period. It was therefore con-

dynamics) cluded that structured preoperative PCA educa-
tion did not affect patient outcome.158 There
• medical history is no doubt, however, that educational concepts
• weight, sex, age should and could be improved in many hospi-
• psychological factors (expectation, pre- tals. As outlined by Chumbley et al., patients
vious experience, distraction) wished to know whether the drug used in PCA
• ethnicity was morphine, they wanted more information
about side effects, needed to be reassured that
Two recent publications addressed, more or PCA was safe, and that they could not overdose
less directly, sex. Women after thoracotomy ex- or become addicted—and they wanted detailed
pressed more postoperative pain early after sur- instructions and diagrams about the
gery, but developed fewer complications, which technique!159
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 Cost-Benefit Considerations
Chen et al. studied the reasons for patients’ One or two publications each year reflect eco-
wishes to continue or discontinue intravenous nomic aspects of patient-controlled analgesia.
PCA after a standard treatment period. Age, sex, So far, no universal agreement has been
type of surgery, duration of PCA use, side effects, reached if costs of drugs and/or equipment,
and pain scores did not affect the decision to personnel salaries, and extra time required for
continue. The reasons given by those who did servicing devices or special monitoring match
not want to restart PCA were minimal pain the outcome, which could be measured by
(51.9%), inconvenient PCA machine (15.6%), fewer complications, reduced hospitalization
ineffective analgesia (11.7%), side effects time, or less chronification, or just by patients’
(11.7%), or wishing to tolerate pain (7.8%). satisfaction (and their recommendation rate
PCA morphine consumption in the 24-hour for this particular hospital).160–167 As has been
period before cessation of PCA was larger in shown in this update, PCA cannot be consid-
patients wishing to restart PCA than in those ered an entity by itself—there are just too many
who did not. The authors concluded that even modifications in use, too many application
cessation of PCA should be individualized.156 modes combined with too many drug interac-
Pain scores are often used for adjusting PCA tions, and so forth, which all influence efficacy
dosing parameters. Bodian et al. demonstrated in an individual setting. Patients are obviously
that VAS scores should best be grouped into aware that good care has its price, and they seem
few categories (ⱕ30, 31–70 and ⬎70) to achieve willing to pay for it.168 Most specialist nowadays
greater clinical significance in clinical trials, and agree that whatever methodology is used,
that patients’ demands for dose corrections results are best when organization is optimal,
were not influenced whether they saw their which requires a well-trained team of nurses and
earlier scores on an old form or filled in a physicians167,169 and adequate education.170
new one.157 This background must always be kept in mind
As already mentioned earlier, special preop- when newer results are discussed, and it might
erative education on PCA did not improve post- explain why common consensus is still far away.
operative analgesia in children, even if they Length of hospitalization and direct medical
liked the additional information.101 Compara- costs for patients recovering from surgery of
ble results were also obtained from a group the abdominal aorta were comparable between
of 60 women undergoing major gynecologic intravenous and epidural PCA.25 Comparable
surgery. Overall analgesic efficacy, side effects, satisfaction and hospital discharge time were
and recovery times were not affected by a struc- achieved for PCEA versus intrathecal mor-
tured preoperative education program. Patient phine after cesarean section, and even if man-
satisfaction in the education group was signifi- power and drug costs were equal in both
cantly better than control during early recovery, groups, the difference in total costs amounted
but without additional benefit in the remaining to 33 Euros (about US$ 29) and was mainly
caused by the more expensive equipment and also the duration of the second stage
required for PCEA.31 The combination of intra- tended to be longer175—not an uncommon
venous PCA with continuous epidural analge- observation with epidural techniques.176 In an
sia produced better pain relief than PCA earlier study the same group of authors did not
alone, reduced postoperative complications, find any indication for higher cesarean section
and allowed faster recovering activities of daily rates in a group of 715 patients receiving either
life. However, the length of hospital stay and PCEA with bupivacaine and fentanyl or intrave-
medical expense were not significantly nous pethidine PCA.177
different.171 PCEA using 0.1% bupivacaine with fentanyl
Knight et al. compared standard and fast- produced adequate analgesia on the first post-
track care pathways in 60 patients undergoing operative day after general, orthopedic, gyneco-
open donor nephrectomy who received, by sur- logic, and plastic surgery in 92.5% of 1,057
geon preference, either ketorolac only, ketoro- patients, of whom 96.2% were free of nausea.
lac plus spinal morphine, or intravenous opioid During a total of 3,858 treatment days, two
PCA. Median hospital stay was 2 days for the patients (0.19%) had an episode of severe respi-
two fast-track ketorolac pathways compared to ratory depression and one patient (0.09%)
3 days for PCA. Delayed oral intake was seen became unarousable. Hypotension occurred in
in 3–6% of patients on ketorolac, but in 83% 45 patients (4.3%). There were no cases of
with PCA. Although resumption of daily activi- epidural hematoma or abscess. From these re-
ties was comparable, the authors calculated a sults, Wigfull and Welchew concluded that
significant difference in mean global cost PCEA was both efficacious and safe on surgi-
($9,394 for the ketorolac only group, $9,238 for cal wards.178
ketorolac plus spinal morphine, and $11,601 Although most PCA devices on today’s
for PCA).172 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
Safety Aspects and Mishaps respiratory depression,181–183 sometimes caused
On the whole, PCA appears to be safe and by ignoring the correlation between opioid
can probably help reduce typical postoperative dose, analgesia, sedation, and the resulting de-
complications.2 Most communications covering pression of the brainstem reticular formation.
the safety aspect are more or less anecdotal, This series was prolonged in the last years by
and it must be assumed that some mishaps hap- three short communications about faulty de-
pened without proper publication. vices or programming errors, some unfortu-
Simopoulos et al. concluded, from a retro- nately with fatal outcomes,184–186 stressing once
spective analysis of 355 medical records, that more the long ago published recommendations
norpethidine central nervous toxicity was best to avoid PCA mishaps by proper selection of
prevented by reducing daily intravenous pethi- patients, adequate monitoring, and thorough
dine PCA doses to 10 mg/kg for not longer education of the staff involved.187
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 Conclusion
the time of first passage of flatus in 51 women The concept of patient-controlled analgesia
and suggested that the favorable pharmacoki- was one of the most important developments
netic profile of PCA could help reduce the in pain management, not simply because it pro-
morphine-induced bowel dysfunction at its vided better analgesia to patients but also be-
therapeutic level.174 In a study of 459 parturi- cause it improved our understanding of pain
ents, epidural analgesia with 0.0625% bupiva- and suffering, and because it forced medical
caine and fentanyl prolonged the active phase care providers to no longer close their eyes.
of labor by 1 hour compared with intravenous There might be more effective strategies for
pethidine PCA. The rate of cervical dilation acute and chronic pain relief than intravenous
was significantly less with epidural analgesia, opioids, but even this insight was strongly
supported by the “incredible” results which 15. Rawal N. Treating postoperative pain improves
continue to be produced in ever increasing outcome. Minerva Anestesiol 2001;67(Suppl 1):
200–205.
numbers.
16. Sentürk M, Özcan PE, Talu GK, et al. The
effects of three different analgesia techniques on
long-term postthoracotomy pain. Anesth Analg 2002;
94:11–15.
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S72 Journal of Pain and Symptom Management Vol. 29 No.

Proceedings of the Symposium “Updates of the Clinical Pharmacology

Introduction cause “these methods do not take into account

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

3. Patient-related factors (kinetics and postoperative period. It was therefore con-

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