Best Practice & Research Clinical Anaesthesiology

Vol. 21, No. 4, pp. 557–573, 2007

doi:10.1016/j.bpa.2007.06.005
available online at http://www.sciencedirect.com

Pain management after craniotomy

Edward C. Nemergut MD
Associate Professor

Marcel E. Durieux * MD PhD

Professor
Department of Anaesthesiology, University of Virginia, USA
Department of Neurological Surgery, University of Virginia, USA

Nizam B. Missaghi MD
Resident in Anaesthesiology
Department of Anaesthesiology, University of Virginia, USA

Sabine Himmelseher MD
Anaesthesiologist
Klinik für Anästhesiologie, Klinikum rechts der Isar, Technische Universität München, Germany

Fear of the side effects of analgesic drugs frequently leads to the under-treatment of post-
craniotomy pain. Nevertheless, this pain continues to be commonly observed, is frequently
severe, and, if unrelieved, may cause distress for the neurosurgical patient and serious compli-
cations for the operative brain. We review recent evidence-based data on pain therapy after
intracranial surgery. Especially when performed at the end of surgery, local anaesthetic scalp
infiltration provides adequate, short-term postoperative pain relief. Opioids, such as morphine
or oxycodone, may be used in the early period after craniotomy. If titrated properly, opioids do
not increase serious side effects as compared with codeine. The non-narcotics ketoprofen, tra-
madol, and paracetamol may be useful as supplemental, opioid-sparing drugs. There is a need for
larger trials to delineate safety and efficacy of analgesic therapies with a focus on short- and
long-term outcomes.

Key words: pain; pain, postoperative; craniotomy; neurosurgery; postoperative complications;

postoperative Nausea and Vomiting.

* Corresponding author. Department of Anaesthesiology, University of Virginia, P.O. Box 800710,

Charlottesville, VA 22908-0710, USA. Tel.: þ1 0434 924 2283; Fax: þ1 0434 982 0019.
E-mail address: [email protected] (M.E. Durieux).
1521-6896/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
558 E. C. Nemergut et al

INTRODUCTION

Surgery and the associated tissue injury and inflammation is almost always associated
with postoperative pain. Historically, postoperative pain has been under-treated
and was often considered to be an undesirable but unavoidable complication of
surgery. More recently, the recognition that poor pain control is associated with
poor outcome and an increase in the incidence of many postoperative complications
has led to clinicians taking a more proactive approach to prevent and treat postop-
erative pain. The Joint Commission on Accreditation of Healthcare Organizations in
the United States has incorporated standards for postoperative pain management
and, in many countries, adequate post-operative pain relief is considered a legal
right.1
Despite these advances in pain diagnosis and treatment, many clinicians consider
intracranial surgery only to be associated with minimal patient discomfort. Indeed,
a frequently cited retrospective chart review reported only minimal pain after brain
surgery; however, this conclusion is based on only 90 minutes of postoperative obser-
vation of craniotomy patients who received more than 500 mg of intraoperative fen-
tanyl.2 To be sure, we now recognize that most intracranial procedures cause
significant postoperative pain. Recent evidence indicates that post-craniotomy pain
is reported as moderate to severe in up to 80% of patients and may persist for several
days postoperatively, depending on the nature of tissue injury.3–8 Persistent headache
remains an underestimated complication after craniotomy.8–10 Despite these facts, ex-
perts and recent surveys increasingly emphasize that post-craniotomy pain continues
to be poorly managed and under-treated.3,6,8,11–13
Recently, Gottschalk et al prospectively studied 187 patients who underwent major
intracranial surgery.8 Nearly 70% of patients experienced severe pain (>4 on a 0–10
scale) during the first postoperative day and 48% on the second postoperative day. The
authors found that despite continued complaints of severe pain, pain was treated only
with high-dose acetaminophen and, in some cases, very small amounts of fentanyl. As
eloquently noted in an accompanying editorial, ‘‘This seems to suggest that the treating
physicians on the one hand believed that they should be able to get by with nonopiate
analgesics (because craniotomy is not painful.), yet on the other hand realized that
their patients suffered and therefore, fearing opiates, prescribed more and more of
the nonopiate analgesic medication’’.14
Three reasons may account for this situation. First, there are specific concerns that
the side effects of potent analgesic drugs may cause miosis, respiratory depression,
nausea, vomiting, and over-sedation. These adverse events may not only interfere
with recovery from anaesthesia and postoperative neurological assessments, but
may jeopardize the cerebral circulation and cerebral dynamics in patients with com-
promised intracranial compliance.15 As all opioids blunt the respiratory response to
hypercarbia, there is concern that opioid-induced carbon dioxide retention will pro-
voke increases in cerebral blood volume with the possible formation of cerebral
edema with associated increases in intracranial pressure (ICP). Sympathetic activation
may increase arterial and intracranial pressures and increase cerebral oxygen con-
sumption. Serious complications, such as cerebral edema, ischemia, intracranial hem-
orrhage, or disruption of the delicate neurosurgical hemostasis may ensue.15 For
example, a retrospective analysis of 11,214 craniotomy patients showed that perioper-
ative systemic hypertension was associated with postoperative intracranial hemor-
rhage (ICH), which prolonged hospital stay and increased mortality.16 Additionally,
 Pain management after craniotomy 559

there may be an increased risk for aspiration, as this population frequently has
compromised pharyngeal and laryngeal reflexes.
Second, there is a lack of standardized, proactive protocols for the assessment and
evaluation of post-craniotomy pain, pain therapy, and patient and caregiver education.
Analgesic therapy and scope of pain after intracranial procedures is actually not in-
cluded in several standard neurosurgical texts. This may in part relate to the fact
that caregivers are faced with the difficulty of diagnosing pain and its severity in
patients with aphasia, altered mental status, or cognitive impairment. Improved aware-
ness of post-craniotomy pain may result in a more proactive approach to pain
management.7,8,14
Third, there is continuing controversy regarding the choice of the ‘‘best’’ anaes-
thetic regimen for intracranial surgery.17–19 Practice patterns using different combina-
tions of anaesthetics and opioids have effects that extend variably into the
postoperative period. This heterogenous approach to neuroanaesthesia precludes
any uniform approach to post-craniotomy pain evaluation and treatment. Many studies
fail to consider the potential differing effects of the drugs used intraoperatively. For
example, remifentanil is frequently used as part of balanced anaesthetic during neuro-
surgical procedures. Remifentanil has several advantages when used in neuroanaesthe-
sia including its quick onset and rapid metabolism. Whereas an anaesthetic that
includes remifentanil may result in a more reliable emergence from anaesthesia and
facilitate early neurologic assessment20–23, the use of remifentanil has been associated
with opioid tachyphylaxis and increased postoperative pain in several different surgical
models.24–26 Nevertheless, significant postoperative pain has been reported in anaes-
thetics that did not utilize remifentanil. In fact, remifentanil was only utilized in 10.9%
of the patients in the series reported by Gottschalk et al.8
In an effort to improve the postoperative care of patients undergoing craniotomy,
we reviewed the evidence available on short- and long-term outcomes of analgesic
therapy following brain surgery. We conclude with an attempt to formulate treatment
options for post-craniotomy pain and provide a brief outlook on further research
requirements.

METHODS

The MEDLINE Library of Medicine database was searched with the date range of 1994
to April 2007. All articles containing the key words pain, brain, intracranial surgery,
supra or infratentorial surgery, craniotomy, craniectomy, neuroanaesthesia, and analge-
sia were searched; for the purposes of this review, only studies with pain after brain
surgery as primary endpoint were included. After English abstract screening, relevant
papers were obtained, and the full article was reviewed. Reference lists of selected ar-
ticles were checked for additional papers. Randomized, controlled trials (RCTs) and
nonrandomized controlled or cohort trials in adults were included; abstracts, letters,
case reports, or unpublished data were not. No minimum sample size was required for
inclusion. Any disputes were resolved by discussion among the authors.
The search yielded 39 articles on pain therapy after intracranial surgery. Seventeen
prospective RCTs were identified; fourteen among them were double-blinded. Arti-
cles assessed pain after a variety of operations, anaesthetic regimens, and analgesic
therapies, and the interpretation of the studies was further complicated by their small
size and heterogeneous design. A quantitative data analysis could therefore not be
performed.
560 E. C. Nemergut et al

RESULTS

The seventeen RCT’s included are shown in Table 1. Some of the articles may have
been underpowered to detect differences in relevant outcomes and the results are
therefore interpreted with this caveat in mind.

Opioid analgesics

Various intra- and post-operative opioid regimens for prevention or treatment of pain
after craniotomy were studied, including various routes of administration, such as in-
tramuscular (IM), subcutaneous (SC), and intravenous (IV) patient controlled analgesia
(PCA). Some studies only focused on analgesia in the immediate post-operative pe-
riod. After similar doses of intra-operative fentanyl, Goldsack et al compared IM
codeine 60 mg with IM morphine 10 mg as rescue analgesics for postoperative pain
in 20 patients per group.27 In the 2-hour assessments after drug injections, morphine
better reduced the need for rescue therapy. Therefore, the authors concluded that
morphine provided more consistent pain control. No differences in respiratory de-
pression, sedation, pupillary size, or cardiovascular effects were noted, but the study
was likely underpowered to assess safety.
Stoneham et al randomized 30 postoperative patients to receive either IM codeine
60 mg or morphine-PCA (1 mg bolus, 10 min lockout, no basal rate) as rescue analge-
sia.28 Within the 24-hour study period, the use of PCA was associated with a trend
toward decreased pain scores. Sedation, respiratory rate, postoperative nausea and
vomiting (PONV), and other adverse events were not different between groups. Nev-
ertheless, the protocol allowed both fentanyl and alfentanil as part of the intraopera-
tive anaesthetic and the drug doses used were not reported.
Sneyd et al randomized 52 adults to three different intra-operative opioid regimens:
alfentanil bolus and infusion, alfentanil bolus and remifentanil infusion, or remifentanil bo-
lus and infusion.29 During the 48-hour post-operative evaluation, IV morphine was of-
fered for rescue on an as needed basis. Not surprisingly, no differences in morphine
needs were observed between the groups. Gelb et al compared the effects of intra-op-
erative fentanyl versus remifentanil combined with morphine on post-craniotomy pain in
91 patients.23 They noted a better quality of emergence after remifentanil-based anaes-
thesia, but earlier needs for rescue analgesia. Initial pain scores were greater after remi-
fentanil, but overall, pain was not different during the 8-hour post-operative study. In
a similar comparison, van der Zwan et al evaluated intra-operative remifentanil combined
with piritramide versus fentanyl-based analgesia.22 The study confirmed more pain and
more need for rescue drugs after remifentanil, but failed to demonstrate a significant dif-
ference in cognitive impairment between the groups.
More recently, Jellish et al randomized 120 patients to receive placebo PCA, mor-
phine PCA, or morphine plus ondansetron PCA after skull base surgery.30 Patients in
all groups received IV morphine for breakthrough pain. Predictably, patients in the pla-
cebo PCA group required more breakthrough morphine; however, there was no dif-
ference in the incidence of PONV between the three patient groups. The use of
morphine PCA was not associated with any increase in patient morbidity or a delay
in neurologic assessment. The authors conclude that the use of morphine PCA is
safe, reduces pain, and does not appreciably increase nausea or vomiting. The study
is noteworthy as the incidence of PONV was not reduced by the inclusion of ondan-
setron in the PCA.30
 Table 1. RCTs on pain treatment after craniotomy.
Authors Study Size Study arms Anesthetic Comment on In case of postoperative Postoperative findings
type regimen opioid (breakthrough) pain reported
Bloomfield Double 36 Procedure Beginning þ End: Thiopental, Sufentanil, Sufentanil Use N/A 1-h Postop Observation:
et al 1998 Blinded Bupivacaine Scalp Infiltr. with Nitrous Oxide, Not Reported Less Pain after
RCT Epinephrine vs NS Infiltr. Isoflurane Bupivacaine
with Epinephrine
Nguyen Double 30 After Skin Closure þ Before Thiopental, Comparable Su- Codeine, 0.5 mg/kg SC 48-h Postop Evaluation:
et al 2001 Blinded Awakening: Ropivacaine Scalp Sufentanil, fentanil Use, but Lower Pain Scores after
RCT Block vs Placebo (NS) Isoflurane N2O Variable Ropivacaine, but Similar
Codeine Need
Biswas Double 41 Preincision: Bupivacaine Scalp Diazepam, Pethidine, Similar intra-op Diclofenac 1 mg/kg IM 48-h Postop Evaluation:
et al 2003 Blinded Infiltration þ IV NS vs NS Thiopental, Nitrous pethidine use if VAS  5 If VAS  8 Pain þ Analgesic Need
RCT Infiltration þ Fentanyl IV Oxide, Isoflurane Beyond 8 hrs of diclofenac, Similar
then Pethidine 0.5 mg/kg
IV q10 min
Law-Koune Double 80 At Skin Closure: Bupivacaine þ Propofol, Sufentanil, Comparable MO Initially: 5 mg, until First 2-h Postop: More
et al 2005 Blinded Epinephrine. Infiltration vs Nitrous Oxide, Sufentanil Use VAS < 3 Then: MO-PCA, Need for MO after NS
RCT Ropivacaine þ Epinephrine. vs Sevoflurane 1.5 mg, 8 min LO 16-h Postop Evaluation:

Pain management after craniotomy 561

NS Scalp Infiltration MO Need þ Pain Scores
Similar
Goldsack Double 40 Postop, On Demand: Morphine Thiopental, Fentanyl, Similar Same as Study Arms 120-min Post-Injections:
et al 1996 Blinded 10 mg IM vs Codeine 60 mg IM Nitrous Oxide, Fentanyl Use Less Dosing Frequency
RCT Isoflurane with MO, No Significant
Adverse Effects after MO
or Codeine
Bala Double 40 After Skin Closure þ Before Thiopental, MO, Intraoperative MO Diclofenac 75 mg IM, Lower pain scores in
et al 2006 Blinded Awakening: Ropivacaine Scalp Nitrous Oxide, use not reported then Tramadol bupivacaine group with
RCT Block vs Placebo (NS) Isoflurane 50 mg IV less need for rescue
medications
(continued on next page)
 562 E. C. Nemergut et al
Table 1 (continued)
Authors Study Size Study arms Anesthetic Comment on In case of postoperative Postoperative findings
type regimen opioid (breakthrough) pain reported
Stoneham RCT 30 Postop, On Demand: MO-PCA, Propofol, Nitrous Sufentanil or Same as Study Arms 24-h Postop Evaluation:
et al 1996 1 mg, 10 min LO vs Oxide, Isoflurane Alfentanil, Doses Pain, Sedation, and
Codeine 30e60 mg, IM Not Reported Respiratory Rates Similar
Sneyd RCT 52 Intraop IV Opiate Comparison Propofol, N/A MO, 2 mg IV, every 5 min, 48-h Postop Evaluation:
et al 1998 Alfentanil B þ Inf vs Alf B þ Inf þ Nitrous Oxide max 10 mg Similar Pain Scores
Remifentanil Inf vs Remifentanil
B þ Inf
Jellish RCT 120 Postop: Placebo-PCA vs. Thiopental, Intraop fentanyl MO 2 mg IV, every Decreased pain in MO-
et al 2006 MO-PCA vs. MO/Ondanstron Fentanyl, doses not 10 minute until pain PCA and MO/Ondansetron
PCA Sevoflurane reported score < 4 PCA groups Addition of
Nitrous Oxide Ondansetron did not
reduce PONV
Rahimi RCT 27 Postop Comparison Rofecoxib Not specificed N/A As needed: Oxycodone/ Opiate consumption, VAS
et al, 2006 vs. on demand po oxycodone/ Paracetamol (5/325 mg) scores, length of stay
paracetamol þ IV MO 1-2 tabs po and/or MO lower in Rofecoxib group
1-2 mg IV
Gelb Double 91 Intraop IV Opiate Comparison Thiopental, Nitrous N/A As Needed: Codeine 8-h Postop Evaluation:
et al 2003 Blinded Remifentanil (0.2 m/kg/min) þ Oxide, Isoflurane 30e60 mg IM or Demerol Remifentanil þ MO:
RCT MO (0.08 mg/kg) vs Fentanyl 50e150 mg IM every 4 h Faster Recovery, Sooner
(0.4 mg/kg/min) Need for Rescue Drugs,
More Initial Pain
Van der Double 40 Intraop IV Opiate Comparison Thiopental, N/A Piritramide IV as Needed Postop: Remifentanil: More
Zwan Blinded Remifentanil þ Piritramide Isoflurane, Pain þ Greater Need for
et al 2005 RCT (0.1 mg/kg) vs Fentanyl Nitrous Oxide Rescue Drug
Ayoub Double 50 Postop bupiviaine þ lidocaine Propofol Similar codeine Codein SQ 30e60 mg No difference between
et al 2006 Blinded vs. 0.1 mg/kg MO at dural Remifentnail use every 4 h scalp block and MO
RCT closure Sevoflurane
Jeffrey Double 75 Postop, On Demand, IM: Propofol, Alfentanil Use Same as Study Arms 48-h Postop Evaluation:
et al 1999 Blinded Codeine 60 mg vs Tramadol Alfentanil Not Reported Lower Pain Scores with
RCT 50 mg vs Tramadol 75 mg Codeine, More Sedation
and PONV after
Tramadol 75 mg IM
Tanskanen RCT 45 Postop, TID: Ketoprofen 42 Patients: Opioid Use Not Oxycodone-PCA, 24-h Postop Evaluation:
et al 1999 100 mg vs Paracetamol 1000 mg, Isoflurane, Reported 0.03 mg/kg, Less Breakthrough after
First Dose Rectally, Then Orally Fentanyl, max 3 x per h, Ketoprofen than
Nitrous Oxide 10 min LO Paracetamol
Ferber Double 35 Postop IV Tramadol: 0.75 mg/kg N/A N/A Tramadol IV (Same 30-min Post-Injection:
et al 2000 Blinded (3 min) vs 1.0 mg/kg (5 min) vs Dose as Resp. Better Satisfaction with
RCT 1.0 mg/kg (10 min) Study Arm) Analgesia after 1.0 mg/kg
Tramadol
Verchère Double 64 At 1 h before End of Surgery: Propofol, Comparable Postop, All Patients: 24-h Postop Evaluation:
et al 2002 Blinded Propacetamol 30 mg/kg IV vs Remifentanil Remifentanil Use Propacetamol 30 mg/kg Propacetamol Alone
RCT Tramadol 1.5 mg/kg IV vs IV, every 6 h; Studied: Insufficient Less Need
Nalbuphine 0.15 mg/kg IV Propacetamol Alone vs for Nalbuphine than for
Propacetamol þ Tramadol Tramadol Tramadol:
vs Propacetamol þ Trend to More PONV

Pain management after craniotomy 563

Nalbuphine Dose as in
Study Arms
Alf ¼ alfentanil, B ¼ bolus, Inf ¼ Infusion, Infiltr. ¼ Infiltration, Intraop ¼ intraoperative, LO ¼ lockout, MO ¼ morphine, N/A ¼ not applicable, N2O ¼ nitrous oxide,
NS ¼ normal saline, PCA ¼ patient-controlled analgesia, PONV ¼ postoperative nausea and vomiting, Postop ¼ postoperative, RCT ¼randomized, controlled trial.
564 E. C. Nemergut et al

In summary, morphine offers better analgesia and more consistent pain reduction
than does codeine. Serious complications were not reported, but no trial was pow-
ered to detect differences in safety issues associated with opiates. It is noteworthy
that neither the safety of morphine nor that of codeine has been studied so far in
this setting.

Local anaesthetics

Six studies investigated the effects of intraoperative scalp infiltration or scalp nerve
blocks with the local anaesthetics (LA) bupivacaine or ropivacaine.31–36 All reported
short-term benefit. Bloomfield et al randomized 36 patients to bupivacaine versus nor-
mal saline (NS) pre-incisional scalp infiltration. They noted lower pain scores in the first
postoperative hour after bupivacaine, and a blunted intraoperative hemodynamic re-
sponse to surgery.32 Nguyen et al studied 30 patients randomized to scalp blocks
with ropivacaine or NS. Over a 48-h postoperative period, pain scores were lower after
ropivacaine, but no difference in time to first rescue analgesia or in need for rescue
drugs was noted.33 Biswas et al studied 41 patients, comparing intravenous (IV) fentanyl
with bupivacaine scalp infiltration. Overall need for rescue analgesics was similar in both
groups, but a trend toward a delay in the need for rescue after bupivacaine was found
during the 48-h observation.31 Yildiz et al found no advantage to a skull block when com-
pared to pre-pinning treatment with a large intravenous bolus of fentanyl in a series of
120 patients; however, the effect on postoperative pain was not reported.37
Law-Koune et al studied repeated scalp infiltrations with bupivacaine, ropivacaine,
or placebo.34 While the patients in the placebo group requested more morphine to
treat break-through pain, pain scores and morphine need were similar during the
16-h evaluation after surgery.
More recently, Ayoub et al evaluated the efficacy of scalp block after remifentanil-
based anaesthesia in a group of 50 patients.35 In this double-blind trial, patients were
randomized to either a scalp block with bupivacaine and lidocaine at the end of sur-
gery or 0.1 mg/kg morphine at the time of dural closure. Breakthrough analgesia
was provided with subcutaneous codeine to patients in both groups. Pain scores
were similar between the two groups. Total codeine was also similar and the time be-
fore administration of the first dose of codeine was not statistically different between
groups. Postoperative hemodynamics were also similar in both groups. The incidence
of nausea and vomiting was slightly more frequent in the morphine group, but the oc-
currence of confusion did not differ between groups. The authors concluded that
a scalp block provided a quality of transitional analgesia that is similar to that of
morphine with the same postoperative hemodynamic profile.35
Similarly, Bala et al randomized 40 patients to receive a scalp block with bupivacaine
or placebo after skin closure in 40 patients undergoing supratentorial craniotomy.36
Intramuscular diclofenac or intravenous tramadol was administered as rescue analge-
sic. Moderate to severe pain was more common among patients who did not receive
a skull block and thus they required rescue medication more frequently. Unfortunately,
after six hours pain scores were similar.36
In summary, scalp infiltrations may help to reduce pain in the early post-operative
period and may stabilize the hemodynamic profile by blunting sympathetic responses
to intraoperative stimulation. Nevertheless, postoperative effects are brief and not
clinically superior to opioids, independent of whether infiltrations are applied prior
to incision or are repeated.
 Pain management after craniotomy 565

Non-opiate analgesics and tramadol

Paracetamol (acetaminophen) has been studied as a sole analgesic or in combination

with other drugs. It appears to be an attractive choice because it does not possess ad-
verse effects such as sedation, respiratory depression, or pupillary changes. Tramadol is
also attractive for similar reasons. Tramadol has weak m-opioid receptor activity and re-
duces 5-hydroxytryptamine and norepinephrine reuptake in descending inhibitory pain
pathways. Jeffrey et al studied postoperative on-demand analgesia in 75 patients ran-
domized to receive IM codeine 60 mg, IM tramadol 50 mg, or IM tramadol 75 mg as res-
cue analgesics.38 In the 48-hour postoperative evaluation, codeine was consistently
associated with lower pain scores and less need for breakthrough pain therapy than ei-
ther dosing regimen of tramadol. After 75 mg of tramadol, the incidence of sedation and
post-operative nausea and vomiting (PONV) was greater than after the other drugs. Be-
cause the investigators also noted an increased frequency of analgesic requirements, an
analgesic effect of higher dose tramadol was suspected.
Verchère et al studied 64 patients randomized to one of three IV combinations: prop-
acetamol (a pro-drug of paracetamol), propacetamol and tramadol, or propacetamol
and nalbuphine.39 At 1 hour before the end of surgery, patients received propacetamol
30 mg/kg, tramadol 1.5 mg/kg, or nalbuphine 0.15 mg/kg. During the first 24 postoper-
ative hours, all patients received propacetamol 30 mg/kg every 6 hours and tramadol or
nalbuphine as demanded for rescue analgesia in the respective study group. Due to in-
sufficient pain control, the paracetamol-only arm had to be terminated prematurely. The
other groups had similar pain scores, but nalbuphine was less often requested than tra-
madol, indicating that pain control with nalbuphine was more consistent. There also was
a trend toward a higher incidence of PONV after tramadol.
In 45 randomized patients, Tanskanen et al compared the effects of three scheduled
postoperative doses of paracetamol and the non-steroidal anti-inflammatory drug
(NSAID) ketoprofen on post-craniotomy pain.40 For rescue analgesia, oxycodone-
PCA was provided. Although pain scores were comparable, patients in the paraceta-
mol group required more frequent oxycodone rescue in the 24-hour postoperative
period. No adverse effects on sedation or neurological status were noted. In the
post-operative period, Ferber et al compared 35 patients randomized to three regi-
men of IV tramadol, 0.75 mg/kg over 3 min, or 1.0 mg/kg over 5 or 10 min.41 Analgesia
was assessed during a 30-minute post-injection period. The authors noted dose-
dependent effects: 50% of patients receiving 0.75 mg/kg and 88% receiving 1 mg/kg
of tramadol reported satisfactory pain control, while ICP, blood pressure (BP), and
carbon dioxide retention were unchanged.
More recently, Rahimi et al investigated the efficacy of daily Rofecoxib, a cyclooxy-
genase-2 (COX-2) inhibitor, to reduce postoperative pain in a series of 27 patients
presenting for craniotomy.42 Patients were randomized to receive either daily rofe-
coxib or placebo. Breakthrough pain medications for patients in both groups included
oxycodone and acetaminophen 5/325 mg, 1 to 2 tablets every 4 hours as needed, and
intravenously administered morphine, 1 to 2 mg every 2 hours as needed. Patients in
the control group had significantly higher visual analog scale (VAS) scores, increased
length of stay (LOS), and increased narcotic use compared with the rofecoxib group.42
The control group also had increased hospitalization costs when compared with the
rofecoxib group. Unfortunately, rofecoxib was voluntarily pulled from the worldwide
market on September 30, 2004 and is no longer available. Nevertheless, COX-2 inhib-
itors, which have no adverse effect on platelet function, remain an attractive option for
566 E. C. Nemergut et al

the treatment of postoperative pain. Celecoxib, the only COX-2 inhibitor currently
available, may provide an attractive option; however, its efficacy has not yet been
established in the post-craniotomy patient population.
In summary, paracetamol and ketoprofen may be used as supplemental analgesics
after craniotomy. Tramadol and opioid agonist-antagonists such as nalbuphine may
also have a supplemental role; however, an IV formulation of tramadol is not available
in the United States at this time. There is some data to support the efficacy of COX-2
inhibitors in the treatment of post-craniotomy pain; however, other studies utilizing
Celecoxib are needed.

Other analgesics

There is little data regarding the efficacy of other drugs with analgesic properties in
brain surgery. In almost 200 neurosurgical patients Wilkund et al noted that physostig-
mine maintains analgesia in the immediate post-operative time when combined with
naloxone to reverse opioid-, neuroleptic- and benzodiazepine-associated sedation.43
In a recent double-blind randomized controlled trial, the alpha-2 agonist clonidine pre-
vented shivering after craniotomy when applied at 1-hour before the end of surgery,
but did not change the secondary outcome parameter ‘‘postoperative pain’’ in a 2-
hour post-surgical observation period.44 The N-methyl-D-aspartate (NMDA) antago-
nist ketamine was studied in a double–blinded randomized controlled trial to assess its
effects on the circulatory response to skull-pin placement in neurosurgery.45 One IV
subanaesthetic dose of 0.5 mg/kg of racemic ketamine significantly attenuated the he-
modynamic response only when combined with lidocaine scalp infiltration.

DISCUSSION

We are faced with the evidence from only a few heterogeneous trials on pain therapy
after craniotomy, each only evaluating short-term outcomes in small patient numbers.
Appropriate evaluation is complicated by weaknesses in study design and/or method-
ology. There are no trials on therapy or measurement of pain in patients with neuro-
cognitive status changes. Nevertheless, recent surveys3,6,46 and expert opinion11,12,14
underline the point that post-craniotomy pain is perceived to be significant and stress
a growing interest and need for post-craniotomy pain management strategies.
One problem common to all the studies cited in this review is the fact that all crani-
otomies are evaluated as being ‘‘the same.’’ Whereas some authors have attempted to
differentiate between supra- and infratentorial tumors, precious little information re-
garding the specifics of the surgical approach is included by most authors. It is possible
that the variability in patient pain reporting reflects differences in the specifics of a cra-
niotomy that are not yet understood.14 That is to say that all surgical approaches might
not be equal in their ability to produce pain. For example, we speculate that a temporal
approach to a tumor that includes disruption of the temporalis muscle might be signif-
icantly more painful than a bicoronal or bifrontal approach that does not injure the mus-
cle. This may explain some of the observed variability in patient complaints.8
Despite this background, it is the caregiver’s task to prevent a vicious cycle that can
potentially develop from inadequate pain control: patient agitation, the adverse effects
of inappropriate analgesic drugs, and pain-related (or pain treatment-related) complica-
tions. Each of these may potentially exacerbate neurologic injury in the post-craniotomy
setting. On the other hand, a poor neurologic status may mimic untoward effects of
 Pain management after craniotomy 567

analgesic drugs and lead to ineffective pain therapy (Figure 1). Various negative clinical
outcomes and associated economic burdens may result.47 Attempting to minimize
the pain score may thus not always be the most desirable or the only goal of pain therapy
after intracranial surgery. The delicate task at hand is the provision of a level of pain relief
that does not come at the expense of a decline in the patient’s neurologic condition.14
With this objective in mind, the data can be discussed as follows.
Scalp infiltrations afford early, temporary post-surgical pain relief. When applied or
repeated at the end of surgery, they may have an opioid-sparing effect post-opera-
tively.34 As post-craniotomy pain appears to be especially severe during the first
post-surgical hours3–6,48 and may mainly originate from somatic tissue damage of peri-
cranial muscles4,9,10, scalp infiltrations may serve as an excellent initial approach to
post-surgical pain; however, their benefits must be weighed against risks inherent of
LA, such as accidental intravascular injection with seizure induction, inadvertent facial
nerve blockade, ptosis, cranial hematoma, and other toxicity issues. Pharmacokinetic
studies on plasma levels after LA scalp infiltration imply that systemic absorption oc-
curs within minutes and in amounts of more than 50% of the dose infiltrated due to
the rich vascularity of the scalp.49–51 A maximum of 225 mg of ropivacaine with or
without epinephrine was recommended49,50, which fits the limits for central nervous
system and cardiovascular toxicity in volunteers receiving IV LA infusions.52 Whereas
scalp infiltrations are likely to be safe in the hands of experienced providers, and novel
agents with less toxicity such as levobupivacaine51 may increase the margin of safety,
they will probably not induce longer-lasting analgesia with currently available drugs.
In the postoperative period, the opiates morphine, codeine, and oxycodone pro-
vide pain relief when LA and less potent analgesics such as tramadol, paracetamol
or ketoprofen do not achieve adequate analgesia.33,34,38,40 The methodologic weak-
ness observed in the trials reviewed is that intraoperative use of opioids was variable,
and that adequate comparisons in intraoperative opioid consumption with correction

Poor Neurologic status

Neurologic Injury

Complications

Sedation, Hemodynamic + Sympathetic Discharge,

Respiratory Depression Agitation
Nausea / Vomiting

Adverse Effects Inadequate

of Analgesic Drugs Treatment

Pain
After Craniotomy

Figure 1. Inadequate treatment of pain after craniotomy, apart from its detrimental psychological aspects,
can have negative effects on the patient’s neurologic status because of agitation and hemodynamic changes.
On the other hand, potent analgesic drugs have side effects (respiratory depression, nausea/vomiting) that
can negatively impact neurologic recovery after surgery. If an appropriate balance between these issues is not
reached, neurologic injury can result.
568 E. C. Nemergut et al

for equianalgesic doses were not conducted between study arms.28,29,38,40 Intraoper-
ative opiates may not only have analgesic effects that last into the postoperative pe-
riod, but may also activate pronociceptive systems and induce rapid opiate-related
tolerance phenomena.53 Not surprisingly, after similar use of one intra-operative opi-
oid, postoperative morphine provided better pain control than codeine.27 Unfortu-
nately, morphine, codeine, and other analgesics were often delivered via the IM route.
This is of very questionable value, because IM injections are associated with pain on in-
jection, slower onset and more variable absorption than IV administration.11,54
Our data and in a recent survey of centers in the UK suggest that codeine con-
tinues often to be used as first-line analgesic after craniotomy.3 Although this practice
represents a relic of the past (before availability of monitoring with oximetry and use
of naloxone), it should be noted most of codeine’s analgesic efficacy is derived from
the 5–15% of that is metabolized to morphine by hepatic CYP2D6. Codeine’s efficacy
is significantly affected by inter-individual and ethnic differences in CYP2D6 demethy-
lation capacity and the potential for individual patients taking CYP2D6 inhibitors. In-
deed, 15% of Caucasians do not experience any effect from codeine due to normal
genetic variation.55 Moreover, codeine also carries safety risks and induced cardiovas-
cular collapse and respiratory arrest after neurological surgery.56 Comparing codeine
and morphine, our data did not show an increase in serious adverse effects such as
sedation or respiratory depression after morphine27,28 but no study was adequately
powered to assess safety issues. Sedation scores also did not change with use of an
IV oxycodone-PCA.40 The lack of sedation or respiratory depression may therefore
suggest the safety of prudent and titrated opioid use with adequate monitoring. To
prevent hemodynamic activation and stress resulting from excessive pain, morphine
may also be used as transitional analgesic after remifentanil-based anaesthesia.
Remifentanil has become popular in neurosurgery because it provides circulatory sta-
bility during intense surgical stimulation while allowing for rapid emergence without re-
spiratory depression. Nevertheless, patients are prone to develop hypertension and
pain after craniotomy with remifentanil15,20,57,58, and request early pain therapy.22,23
To prevent significant increases in blood pressure (potentially resulting in intracranial he-
matoma15), potent opioids may thus be necessary. In conclusion, morphine provides
better analgesia than codeine in the post-craniotomy setting. With spontaneous respi-
ration, opioids carry inherent risks for serious complications after brain surgery, but may
be used with careful monitoring and prudently titrated to individual patient needs.
In contrast to children59, our review shows that even repeated doses of paraceta-
mol are insufficient for relief of early post-craniotomy pain in adults.8,39 In combined
approaches, paracetamol and ketoprofen may reduce the need for more potent anal-
gesics. When used alone, ketoprofen provides better analgesia than does paraceta-
mol40, but its effect on platelet function after brain surgery is unclear.
While potentially increasing the incidence of an intracranial hematoma secondary
to the anti-platelet effect of non-selective NSAIDs such as ketoprofen remains a con-
cern46, there is no specific data suggesting that the use of NSAIDs increase the inci-
dence of an intracranial hematoma. In a retrospective study of 2305 patients
undergoing intracranial procedures, 50 (2%) patients developed an intracranial hema-
toma postoperatively.60 Of these, 90% presented in the first 6 hours after surgery,
likely representing inadequate hemostasis at the time of closure. Thus, it may be rea-
sonable to withhold NSAIDs for the first 6 postoperative hours and administer them
later; however, an intracranial hematoma is associated with significant morbidity and
mortality and absence of evidence to suggest NSAIDs are unsafe should not automat-
ically imply safety. Their use should be carefully considered.46
 Pain management after craniotomy 569

Tramadol does not have a clear benefit over codeine: it shows less analgesic efficacy
while inducing a higher incidence of PONV, and at higher doses it increases seda-
tion.38,39 As vomiting can induce sharp increases in ICP and is, associated with the
risk of intracranial hematoma and other neurological injury61, it is a troublesome ad-
verse effect. In addition, if ondansetron was used to treat PONV with tramadol, its
analgesic efficacy decreased.62 Our data did not report seizures after tramadol, but
it is known to decrease seizure thresholds. This is important in patients presenting
with risk factors for epileptic activity, especially with higher drug doses and long-
term therapy.63 The risks for tramadol-induced seizures after craniotomy merit fur-
ther study. Thus, tramadol may be used alone or combined with other agents, but
will not provide better analgesia than codeine in early post-craniotomy pain.
Because of their neuroprotective properties, clonidine, dexmedetomidine, IV lido-
caine, or ketamine could be of value as analgesics in this setting. After general surgery,
ketamine has established efficacy as an analgesic53, yet fear of psychotomimetic effects
and ICP increases still exists for craniotomy patients. Nevertheless, under controlled
ventilation and in the presence of GABA-ergic agents, ketamine does not increase
ICP.13 In critically ill neurological patients, ketamine maintains hemodynamic and respi-
ratory stability13, and in awake patients, cognitive impairment with IV opiate-ketamine
PCA is minimal.64

CONCLUSIONS AND TREATMENT OPTIONS

Although evidence from trials tends to lag behind clinical practice, our review exposes
several deficiencies within the literature on pain management after craniotomy. First,
the evidence is very limited, and data are confounded by methodologic weaknesses.
No large trials on safety and efficacy issues with pain assessments using standardized
or widely accepted pain measurement tools have been performed. There is no evalu-
ation of postoperative recovery or complications related to inappropriate pain ther-
apy. Second, our analyses confirm the widely varying level of post-craniotomy pain,
and thus, the variable need for analgesia. Trials have not examined intraoperative an-
aesthetic regimens and did not differentiate between varying levels of tissue damage
induced by the technical demands of the surgery performed. Third, there are no trials
investigating effects of pain therapy on long-term outcomes, although, adequate post-
surgical analgesia has been suggested as a factor for a better prognosis with respect to
persistent headache after craniotomy.9,10 Fourth, no trials studied post-craniotomy
pain in patients with neurocognitive status changes.
The data available do not allow us to define therapeutic standards or treatment
guidelines during the early postoperative period. As a treatment option, opioids
such as morphine or oxycodone and opioid agonists-antagonists such as nalbuphine
may be used. With careful monitoring and titrating to individual patient’s needs, po-
tent opioids do not appear to induce more serious side effects than does codeine.
Tramadol has weak opioid activity as well as other analgesic properties and may be
used alone or in combination with other analgesics with special attention to its po-
tential to increase the risk of PONV and lower the seizure threshold. The non-
narcotic paracetamol and NSAIDs such ketoprofen are useful analgesic supplements.
When combined with other analgesics, they may spare opioids, but the potential of
NSAIDS to induce bleeding complications after craniotomy warrants study.
570 E. C. Nemergut et al

Practice points

 Up to 80% of patients experience moderate to severe pain after a craniotomy

and this pain may persist for several days postoperatively.
 Post-craniotomy pain is often under-treated by clinicians concerned about the
sedative side effects of opioid analgesics.
 Opioids such as morphine or oxycodone are effective analgesics and do not
appear to induce more serious side effects than does codeine.
 The infiltration of local anaesthetic either into the wound or as part of ‘‘scalp
block’’ provides short-term reduction in pain scores and the need for opioid
analgesics.
 Tramadol, paracetamol (or acetaminophen), ketoprofen (and other NSAIDS)
may reduce the need for opioid analgesics but often do not provide adequate
analgesia when used a single agent.

OUTLOOK

Future research studies should focus on the obvious need for delineating safety and ef-
ficacy issues of analgesic therapy on short- and long-term outcomes after craniotomy.
The conclusions drawn from the currently available data may be considered in future
study designs and used to determine sample size for such trials. There is a common clin-
ical sense that pain control cannot be examined in isolation in our efforts to improve
postoperative care of post-craniotomy patients: intraoperative and surgical data must
also be evaluated. As analgesic therapies evolve and other aspects of postoperative
care improve, the next phase of trials may be driven by the overall goal of regaining
‘‘best physiologic function’’ as early as possible after craniotomy. In the general surgical
population, early oral fluid administration, enteral nutrition, early mobilization and im-
proved pain therapy has resulted in shortened hospital stay and a decrease in postoper-
ative mortality. Until these processes and others have been optimized in the
postoperative care of patients undergoing intracranial surgery, it may be impossible
to show the benefits of post-craniotomy pain therapy.

Research agenda

 The adverse effect(s) of inappropriate or ineffective perioperative analgesia on

patient outcome must be evaluated to properly assess and evaluate novel
treatments.
 The effect perioperative NSAIDS on the incidence of intracranial hematoma
after craniotomy must be systematically evaluated so clinicians may make evi-
dence-based decision regarding the use NSAIDS after neurosurgery.
 Further research regarding the nature of post-craniotomy pain is needed.
Specifically, researchers should endeavor to establish patient- and procedure-
based risk factors for severe pain.
 Methodologies for evaluating post-craniotomy pain in patients with altered
neurocognitive status must be established.
 Pain management after craniotomy 571

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