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doi:10.1093/bja/aer458
Summary. Relief of acute pain during the immediate postoperative period is an important
Editors key points task for anaesthetists. Morphine is widely used to control moderate-to-severe postoperative
Titration of morphine i.v. pain and the use of small i.v. boluses of morphine in the post-anaesthesia care unit allows a
is used widely for rapid titration of the dose needed for adequate pain relief. The essential principle of a
treatment of pain in titration regimen must be to adapt the morphine dose to the pain level. Although
post-anaesthesia care morphine would not appear to be the most appropriate choice for achieving rapid pain
Pain control after surgery remains a challenge.1 Despite the A titration regimen must avoid both over- and under-dosing.
development of multimodal strategies and evidence-based Although morphine would not appear to be the most obvious
recommendations regarding the use of non-opioid analge- choice for achieving rapid pain relief, it has been assessed in
sics, opioids are often required in the postoperative many studies of immediate postoperative pain management
period.1 3 In the majority of patients requiring potent using titration.6 10
analgesics in the postoperative period, morphine is both effi- Lipophilic opioids such as fentanyl, alfentanil, or sufentanil
cacious and acceptable. Morphine is a non-selective m-opioid are more potent than morphine and have a more rapid onset
receptor agonist that acts directly on the spinal cord and via of action but the duration of analgesia of these drugs is
the descending projections of the periaqueductal grey shorter.5 This review focuses on the i.v. titration of morphine
matter to the rostral ventromedial medulla and to the in the immediate postoperative period. It addresses the
dorsal horn of the spinal cord.4 pharmacological basis of i.v. morphine, clinical use in the
However, clinical studies of morphine for postoperative post-anaesthesia care unit (PACU), the relationship
analgesia have shown wide intra- and inter-individual vari- between pain scores and morphine requirements, adverse
ability in morphine plasma concentration and a wide range effects, and limitations of the technique.
of morphine requirements for postoperative pain. The use The search strategy used involved two electronic data-
of i.m. or s.c. morphine in the immediate postoperative bases [PubMedw (MEDLINE/Index Medicus) and the Cochrane
period is usually not appropriate because of the time delay Controlled Trials Register] which were searched for studies
between morphine administration, morphine absorption, published between 1966 and June 2010. The medical
blood concentration, and analgesic effect (Fig. 1).5 I.V. ad- subject heading terms used for the search were post-
ministration ensures complete bioavailability and high drug operative opioid titration (including morphine or other
concentrations can be achieved promptly. Bolus doses opioids), postanaesthesia care unit, or both. Studies were
given i.v. at fixed time intervals will result in drug accumula- identified from databases and by hand-searching reference
tion but also achieves an efficient therapeutic concentration. lists from review articles and original published articles to
& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
BJA Aubrun et al.
350 30 0.14
250
20 0.10
200
15 0.08
150
10 0.06
100
5 0.04
50
0 0 0.02
0 1 2 3 4 5 6
Time (h)
50 25
40 20
Fig 2 Simulations of Ce obtained after i.v. injection of alfentanil/
30 15 remifentanil (blue), sufentanil/fentanyl (green), and morphine
(pink). Units are arbitrarily normalized by the area under the
20 10
Ce time curve. The time to Cemax, the peak concentration in
10 5
the effect compartment, is 2, 6, and 20 min, respectively, for
100 10
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I.V. morphine titration BJA
nucleotide polymorphisms (A118G) in the m-receptor gene
Table 1 Pharmacology of commonly used opioids and relative are associated with decreased potency of morphine and
CNS concentration profiles after i.v. administration.4 6 Relative
M6G, with increasing morphine dosage requirements, and
duration of action, time for which the relative CNS concentration
exceeded 80% of its maximum value; time to relative onset, time
altered efficacy of m-opioid agonists and antagonists.15 16
taken to initially reach 80% of the maximum concentration. Data However, pharmacogenetics may explain ,50% of the
are from Mazoit and colleagues13 observed inter-individual variability and major differences in
the sensitivity to pain seem to be the major factor.14
Morphine Fentanyl Alfentanil A pharmacokinetic pharmacodynamic study6 showed
Potency (vs 1 100 10 20 that the inter-subject variability in the dose required for
morphine) half an initial visual analogue scale (VAS) was .300%.
pKa 8.0 8.4 6.5 Thus, patient sensitivity to pain remains the most important
Plasma protein 30 35 84 90 cause of variability. This is the major justification for using
bound (%)
titration to achieve adequate analgesia in each patient. A
Volume of 2 4 3 5 0.4 1.0
study of morphine titration in the postoperative period
distribution
(litre kg21) attempted to identify the covariates significantly affecting
Blood brain 120 180 6 1 the dose leading to analgesia and to sedation.6 The mor-
equilibration phine ED50 for analgesia was about 10.2 mg, which agrees
rate (min) well with previously reported values.17 The factors which
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BJA Aubrun et al.
the interval between boluses, the limitation (or not) of the sedation. In the protocol proposed, morphine titration is
total dose of morphine i.v. injected, and the criteria to stop stopped if the patient becomes sedated (Ramsay
titration. score .2), has a ventilatory rate of ,12 bpm, or an
oxygen saturation of ,95%, or has a serious adverse event
(allergy, hypotension, severe vomiting). Using this titration
Clinical use in the PACU protocol, the percentage of patients with pain relief
I.V. administration of opioids is usually recommended for (defined as a pain level 30 mm) may be up to 98% with
acute pain relief in the immediate postoperative period and a very low incidence of severe adverse events such as
the use of small i.v. doses of morphine (,5 mg) allows severe ventilatory depression (,1%).7 10 18 The administra-
rapid titration to adequate pain relief. The challenge is to ad- tion of small boluses of morphine probably increases the
minister the second and subsequent doses in a manner that time to pain relief but decreases the risk of adverse events
takes account of the residual effects of the first dose. An im- related to morphine dose accumulation. Repeat i.v. doses
portant consideration is factors which may predict morphine of 5 or 10 mg, rather than doses of 2 or 3 mg, is inappropriate
requirements in the PACU. A study of 149 patients undergo- in an opioid-naive patient.7 21 23
ing various non-cardiac surgical procedures identified that
ethnicity (Caucasians), emergency surgery, major surgery,
The relationship between pain score and
surgery exceeding 100 min, and pain score on arrival in the
PACU (moderate-to-severe pain) were independent predictive morphine requirements
factors of early morphine requirements in the PACU.22 For i.v. morphine titration, the relationship between the pain
In a patient who was awake in the PACU, the presence of relief, as reflected by the VAS, and time is important. When
pain can be assessed using a VAS or a numerical rating scale. the pain relief process is analysed globally, it appears to be
Pain relief is usually defined as a VAS score of 30 mm. An linear (Fig. 4A).8 10 18 A study of more than 3000 post-
example of an i.v. morphine titration protocol would be operative patients in the PACU found that patients with
when pain increases to .30 mm, i.v. morphine is titrated higher initial VAS required more incremental doses of mor-
i.v. until pain relief is achieved using a short interval phine to reach an acceptable level. The mean (SD) dose for
between boluses (5 min) and no upper limit for the total pain relief was 0.17 (0.10) mg kg21 with a median of four
administered dose (Fig. 3).10 18 If the patient is asleep, no boluses (range: 120).9 Nevertheless, when patients were
attempt is made to awaken him/her and the patient should grouped according to the number of boluses required, each
be considered to have pain relief or morphine-related curve was sigmoid (Fig. 4B).9 In the same way, the
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I.V. morphine titration BJA
A B
100 100
1 bolus
80 80 2 boluses
3 boluses
4 boluses
60 60
5 boluses
VAS
VAS
40 40
20 20
0 0
0 5 10 15 20 25 End 0 5 10 15 20 25 End
Time (min) Time (min)
Fig 4 Relationship between the VAS score [mean (SD)] and time (interval between two boluses was 5 min) during morphine titration and thus
pain relief. (A) Global population. (B) Patients separated into groups according to the number of boluses needed to obtain pain relief.9
that dose ultimately needed to obtain pain relief (threshold Urinary retention 27 (2.6) 17 (2.7)
dose) and then it abruptly decreases. Moreover, a VAS score Respiratory 4 (0.4) 16 (2.6)*
depression
of ,60 is associated with a the subsequent requirement of
Severe respiratory 0 0
only one bolus of morphine.9 The use of i.v. titration is
depression
aided by an understanding of the time course of VAS scores
Pruritus 3 (0.3) 4 (0.6)
during the pain relief process and the pharmacokinetic prop-
Allergy 4 (0.4) 1 (0.2)
erties of i.v. morphine.
Sedation 628 (59.8) 60 (9.6)*
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BJA Aubrun et al.
values ranging from 85% to 94% have been used to define analgesia during i.v. morphine titration.30 31 Support-
respiratory depression.26 As most patients in the PACU ing this are the initiation of pain prevention during
receive supplemental oxygen, an S pO2 ,95% may be consid- surgery and the use of multimodal analgesia in the
ered as an index of ventilatory depression limiting morphine PACU.
titration.7 10 18 Ventilatory rate is considered a more reliable (ii) Stopping morphine titration when the Ramsay score is
and adequate index of hypoventilation in most studies.7 9 10 above 2 limits the risk of ventilatory depression, even if
The threshold value used to define ventilatory depression the causation of sedation is unclear.7 10 18
and to discontinue morphine titration is usually taken as
10 or 12 bpm.23 26 28 This threshold is used in many In conclusion, sedation is frequent during i.v. morphine titra-
studies for safety reasons.7 10 18 Severe postoperative venti- tion even if this effect is often related to pain relief (Table 2).
latory depression (,10 bpm) associated with an impairment The incidence of ventilatory depression is low when the cri-
of consciousness level requires reversal with naloxone until teria to stop i.v. morphine administration are enforced.
the ventilatory rate is .12 bpm in a patient who is awake.
The incidence of severe ventilatory depression is low if a Morphine titration in the elderly
strict protocol for titration is used, particularly with a sed- In elderly patients, a reduced dose of opioids is usually
ation scale; when the level on the Ramsay scale is .2, mor- recommended because of changes in pharmacokinetics
phine titration is stopped.7 10 and pharmacodynamics. There is a 50% reduction in clear-
ance, and a reduction in protein binding,32 and increased
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I.V. morphine titration BJA
surgery confirmed that the dose of morphine (normalized for administered in mg kg21 morphine equivalents, patients in
body weight) was not significantly modified in elderly this study received adequate pain treatment in the recovery
patients.34 In contrast, on the ward after i.v. morphine titra- period.41
tion, there was a significant reduction in the dose of s.c. mor- Most data support the use of titration and confirm that
phine over the first 24 h (236%) and the dose of s.c. the amount required to relieve pain differs from child to
morphine was significantly correlated with age (R 20.15, child. Opioid infusions in children are useful but their
P,0.009).34 Thus, the dose of i.v. morphine during acute dosing and titration require expertise and vigilance. Never-
postoperative titration is not significantly modified in theless, there are limitations to the use of morphine titration
elderly patients, but the dose of morphine given over the in paediatrics: pain scores are not always obtainable in the
first 24 h is reduced by 40%.10 34 Previous studies of the PACU,36 and the validity of self-reported pain intensity
elderly in the postoperative period have assessed the vari- scores may be unreliable making dose adjustment diffi-
ables influencing morphine requirements over a longer cult.36 41 The correct bolus dose adjusted to body weight is
time period using patient-controlled analgesia and not in not established. However, several authors recommend an
the immediate postoperative period using i.v. morphine titra- initial bolus of 100 mg kg21 followed by additional doses of
tion. However, further studies are required comparing mor- 2025 mg kg21 every 5 min until pain relief or sedation
phine requirements in the elderly and frail elderly patients. occurs.37 41 Nevertheless, more studies are required to es-
Patients .90 yr represented ,2% of the elderly population tablish a consensus protocol for morphine titration in
in a previous study.10 A protocol using small boluses of 1 2 young children.
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BJA Aubrun et al.
useful to study morphine titration using a VAS and a numer- 5 Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation
ical rating scale, which is a validated tool in acute and of opioid treatment in acute pain therapy. Clin Pharmacokinet
chronic pain and well correlated with the VAS scale.45 1997; 33: 225 44
Most authors agree that morphine titration should not be 6 Abou-hammoud H, Simon N, Urien S, Riou B, Lechat P, Aubrun F.
Intravenous morphine titration in immediate postoperative pain
limited to three or four doses. However, it is appropriate to
management: population kinetic pharmacodynamic and logistic
define a dose of morphine that triggers an alert and also regression analysis. Pain 2009; 144: 139 46
define failure of morphine titration. For an alert, when a 7 Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative ti-
locally agreed total dose is reached (e.g. 20 mg morphine) tration of intravenous morphine. Eur J Anaesthesiol 2001; 18:
the nurse should seek advice as to whether it is appropriate 159 65
to continue titration or to use an alternative analgesic drug 8 Aubrun F, Langeron O, Heitz D, Coriat P, Riou B. Randomized,
or procedure. Failure can occur when adverse effects placebo-controlled study of the postoperative analgesic effects
require discontinuation of morphine titration before sufficient of ketoprofen after spinal fusion surgery. Acta Anaesthesiol
pain relief is obtained.28 I.V. administration of alternative an- Scand 2000; 44: 9349
9 Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Relationship
algesic drugs, such as nefopam or a small dose of ketamine,
between measurement of pain using visual analog score and
may improve the effects of subsequent morphine titration.46
morphine requirements during postoperative intravenous mor-
Indeed, benefits can be achieved by the combined use of phine titration. Anesthesiology 2003; 98: 1415 21
opioids along with non-opioid analgesics, NSAIDs, and local 10 Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative
anaesthetics. Further studies are required to find the best titration of intravenous morphine in the elderly patient.
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analgesia after total hip arthroplasty. Can J Anaesth 2000; 47: 35 Rivera R, Antognini JF. Perioperative drug therapy in elderly
309 14 patients. Anesthesiology 2009; 110: 1176 81
24 Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified 36 Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous mor-
risk score for predicting postoperative nausea and vomiting. An- phine in postoperative infants: intermittent bolus dosing versus
esthesiology 1999; 91: 693 700 targeted continuous infusions. Pain 2000; 88: 89 95
25 Lvovschi VE, Aubrun F, Bonnet P, et al. Intravenous morphine ti- 37 Allegaert K, Vanhaesebrouk S, Verbessely R, Van den Anker JN. In
tration to treat severe pain in the ED. Am J Emerg Med 2008; vivo glucuronidation activity of drugs in neonates: extensive
26: 67682 interindividual variability despite their young age. Ther Drug
26 Ko S, Goldstein DH, VanDenKerkhof EG. Definitions of respiratory Monit 2009; 31: 411 5
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28 Shapiro A, Zohar E, Zaslansky R, Shabat S, Fredman B. The fre- Anesth 2007; 17: 75674
quency and timing of respiratory depression in 1524 post- 40 Pop RS, Manworren RCB, Guzzetta CE, Hynan LS. Perianesthesia
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29 Paqueron X, Lumbroso A, Mergoni P, et al. Is morphine-induced 91101
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