British Journal of Neurosurgery

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ibjn20

Options to manage postcraniotomy acute pain in

neurosurgery: no protocol available

Carlos Michell Tôrres Santos , Carlos Umberto Pereira , Pedro Henrique

Silveira Chaves , Pábula Thais Rodrigues de Lima Tôrres , Débora Moura da
Paixão Oliveira & Nicollas Nunes Rabelo

To cite this article: Carlos Michell Tôrres Santos , Carlos Umberto Pereira , Pedro Henrique
Silveira Chaves , Pábula Thais Rodrigues de Lima Tôrres , Débora Moura da Paixão Oliveira &
Nicollas Nunes Rabelo (2020): Options to manage postcraniotomy acute pain in neurosurgery: no
protocol available, British Journal of Neurosurgery, DOI: 10.1080/02688697.2020.1817852

To link to this article: https://doi.org/10.1080/02688697.2020.1817852

Published online: 23 Sep 2020.

Submit your article to this journal

Article views: 5

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ibjn20
BRITISH JOURNAL OF NEUROSURGERY
https://doi.org/10.1080/02688697.2020.1817852

REVIEW ARTICLE

Options to manage postcraniotomy acute pain in neurosurgery: no

protocol available
Carlos Michell To^rres Santosa, Carlos Umberto Pereirab, Pedro Henrique Silveira Chavesc, Pabula Thais Rodrigues
de Lima To^rres , Debora Moura da Paix~ao Oliveirad and Nicollas Nunes Rabeloc
a

a
Department of Neurosurgery, Faculdade Estacio de Sergipe (FaSe), Aracaju, SE, Brazil; bDepartment of Neurosurgery, Hospital HUSE, Aracaju,
SE, Brazil; cDepartment of Neurosurgery, UniAtenas Center University, Paracatu, MG, Brazil; dPh.D. in Health Sciences, Aracaju, SE, Brazil

ABSTRACT ARTICLE HISTORY

The physical processes of incision, traction and hemostasis used for craniotomy, stimulate nerve fibers and Received 5 March 2020
specific nociceptors, resulting in postoperative pain. During the first 24 h after craniotomy, 87% of patients Revised 12 July 2020
have postoperatory pain. The rate of suffering pain after craniotomy falls 3% for every year of life. The Accepted 28 August 2020
objective of this study is to review the available therapeutic options to help physicians treating this pain,
KEYWORDS
and discuss pain mechanisms, pathophysiology, plasticity, risk factors and psychological factors. This is a Analgesia; headache;
narrative review of the literature from 1970 to June 2019. Data were collected by doing a search in postoperative; cranial pain;
PubMed, EMBASE, Cochrane Reviews and a manual search of all relevant literature references. The litera- craniotomy; treat-
ture includes some drugs treatment: Opioids, codeine, morphine, and tramadol, anti-inflammatory non-ste- ment outcome
roids such as cyclooxygenase-2 inhibitors, gabapentin. It discusses: side effects, pharmacodynamics and
indications of each drug, anatomy and Inervation of Skull and its Linigs, pathogenesis of pain Post-craniot-
omy, scalp nerve block, surgical nerve injury, neuronal plasticity, surgical factors and chronic post-surgi-
cal pain.

Introduction pain treatment and regular feedback on performance are essential

factors to improve the quality of pain relief after the surgical pro-
Chronic postsurgical pain (CPSP) is a clinical persisting for at
cedure. The authors support a multidisciplinary involvement for
least three months followed by surgical intervention, where add-
this advance.
itional particular neuropathic symptoms are observed. The prob-
The literature indicates that temporary, restricted use of anal-
lem may also be defined as a long-term ‘neuropathic pain.’1,2
gesics in the postoperative period favors a better prognosis, as
The physical processes of incision, traction and hemostasis
analgesics use in excess may result in chronic headaches.5
utilized in craniotomy stimulate nervous terminations and spe-
Remifentanil and opioids are the primary analgesics used to treat
cific nociceptors resulting in postoperative pain.1,2 60–84% of
post-craniotomy pain. However, headache frequently persists and
patients submitted to craniotomy report pain varying from light
this group of drugs seems limited in their effectiveness.15
to severe.3,4 Particular sites of craniotomy and characteristics of
Postcraniotomy analgesic practice across the UK was the sub-
surgical approaches or technique may result in chronic postcra-
ject of a postal questionnaire sent to the senior nurse of every
niotomy pain of different intensities.5 There is a perception that
neurosurgical department.8 Results demonstrated that only 52%
posterior fossa surgery is more painful than supratentorial, how-
of the health services prescribed analgesia regularly, with 48%
ever, Irefin et al.6 reported that infratentorial craniotomy is not
prescribing analgesia as necessary. In 49% of centers, codeine
related with an increased necessity for immediate postoperative
phosphate was combined to paracetamol, in 22% codeine phos-
pain control compared with supratentorial craniotomy or spi-
phate is combined to paracetamol and diclofenac, 9% used
nal surgery.
Recent research7 demonstrates that during the first 24 h after codeine phosphate alone, 4% used morphine with paracetamol
surgery, 87% of patients report pain after craniotomy, and that and diclofenac, 4% used morphine with paracetamol, 4% used
the probability of suffering postcraniotomy pain decreases 3% for morphine alone, 4% used dihydrocodeine with paracetamol and
each year of life. This pain syndrome, despite the introduction of 4% used dihydrocodeine alone.8 Standardized protocol are not
novel drugs and analgesic techniques, is frequently untreated yet offered.16
because of the risks related to medical therapy.8–10
Mordhorst et al.7 noted that the continued use of sevoflurane Methods
and the absence of corticosteroids therapy during anesthesia,
decreased postcraniotomy pain syndrome occurrence by 14,7% This is a narrative review of the literature from 1970 to June
and 11,9%, respectively. 2019 including reports, systematic reviews, all types of study and
Some authors11–13 advocate guidelines to deal with craniot- other literatures concerning acute pain management after crani-
omy pain. According to Bardiau et al.,14 the standardization of otomy. The data were collected by doing a search of PubMed,

CONTACT Carlos Michell To^rres Santos michellfisio@hotmail.com Department of Neurosurgery, Faculdade Estacio de Sergipe (FaSe), Rua Professora Maria
Esther Lima Tavares, 81, CEP 49095-260, Aracaju, SE, Brazil
ß 2020 The Neurosurgical Foundation
2 C. M. T. SANTOS ET AL.
EMBASE, Cochrane Reviews, and a manual search of all pertin-
ent references in the literature. The keywords used were craniot-
omy, postcraniotomy, pain management, analgesia and outcome.
Anatomy and innervation of skull and its linings
The skull region of the forehead is formed by the frontal bone,
which passes backward in the vault of the skull up to the coronal
suture, where it meets the right and left parietal bones.
The scalp consists of five layers: skin, subcutaneous tissue,
epicranium, subaponeurotic areolar tissue and the pericranium.13
Innervation of the scalp and the dura involves: the trigeminal
nerve, including its ganglion, the three principal divisions and
their branches; the upper three cervical nerves; the cervical sym-
pathetic trunk; minor branches from the vagus; minor branches
from the hypoglossus and some twigs from the facial and glosso-
pharyngeal nerves.17
Catecholaminergic nerve fibers are present in human cranial
dura mater. The basal region is more richly innervated than the
calvarial region. Moreover, these nerve fibers are more abundant
in the perivascular dural zone than in the intervascular zone. It
is hypothesized that these catecholaminergic nerve fibers may be
involved in headache.18
Pathogenesis of pain POS craniotomy
The pain is thought to arise from pericranial muscle and soft tis-
sue. Suboccipital and subtemporal routes are associated with the
highest incidence of pain, possibly related to surgical stress in
major muscle tissues.19 Evidence suggests that surgical incision
and other noxious perioperative events may induce prolonged
changes in central neural function that will later contribute to
postoperative pain.20,21
Clinical and experimental evidence shows that noxious stimuli
may sensitize central neural structures involved in pain percep-
tion. Experimental evidence of these changes is illustrated by the
development of sensitization, wind-up or expansion of receptive
fields of CNS neurones, as well as by the enhancement of flexion
reflexes and the persistence of pain or hyperalgesia after inputs
from injured tissues are blocked. It is clear that the perception of
pain does not simply involve a moment-to-moment analysis of
afferent noxious input but is rather a dynamic process that is
influenced by the effects of past experiences. Sensory stimuli act
on neural systems that have been modified by past inputs, and
the behavioral output is significantly influenced by the ‘memory’
of these prior events.22
The transmission of pain from the periphery to the cortex
depends on integration and signal processing within the spinal
cord, brainstem, and forebrain. Sensitization, a component of
persistent or chronic pain, may develop either through peripheral
mechanisms or as a consequence of altered physiology in the spi-
nal cord or forebrain. Molecular and biophysical mechanisms
contribute to the phenomenon of sensitization and persistent
pain, including abnormal tissue growth called neuroma that
arises after traumatic injury, as well as by laceration or nerves
compression. The neuroma’s exaggerated conduction capacity
due to the abnormal action of voltage-gated Na channels leads to
a state of axonal hyperactivity, increasing sensory and nociceptive
perception The persistent depolarization of these axons is con-
ducted to the broth trigeminal nucleus and to the thalamus and
contributes to the increase in pre-existing headache or to the
development of a new condition. Recently, forebrain structures
have been implicated in the pathophysiology of persistent pain.23
Wind-up is a increase in the excitability of spinal cord neuro-
nes evoked by electrical stimulation of afferent C-fibers.
Although it has been studied for the past 30 years, there are still
uncertainties about its physiological meaning. Glutamate N-
Methyl-D-aspartate (NMDA) and tachykinin NK1 receptors are
required to generate windup, and therefore, a positive modula-
tion between these two receptor types has been suggested by
some authors. However, most drugs capable of reducing the
excitability of spinal cord neurones, including opioids and non-
steroidal anti-inflammatory drugs, can also reduce or even abol-
ish wind-up. Other theories involving synaptic efficacy, potas-
sium channels, calcium channels, etc., have also been proposed
as the mechanisms of this phenomenon. Whatever the mecha-
nisms, wind-up has been interpreted as a system for the amplifi-
cation in the spinal cord of the nociceptive message that arrives
from peripheral nociceptors connected to C-fibers. This probably
reflects the physiological system activated in the spinal cord after
an intense or persistent barrage of afferent nociceptive impulses.
Wind-up, central sensitization and hyperalgesia are not the same
phenomenon, although they may share common properties. In
patients with chronic tension type and migraine-like headaches,
including those associated with head injury24 it is postulated that
the serotonergic system may be disturbed. Evidence suggests that
stimulation of GABA receptors in the raphe nuclei decreases the
firing rate of serotonergic neurones. Post-traumatic headaches
manifesting as ‘migraine-like’ in particular are thought to be a
problem of central neuronal hyperexcitability caused by increased
activity of excitatory amino acids, which leads to a spreading
depression of neuronal activity.25
In an analysis of 54 journal articles, Marcus concluded that
serotonin plays an important role in the pathogenesis of head-
ache. Abnormalities in blood vessels have traditionally been
implicated in the pathogenesis of migraine headaches, and exces-
sive muscle contraction in tension-type headaches. It is thought
that changes in serotonin may precede these changes.26
An increased understanding of the central changes induced by
peripheral injury or noxious stimulation should lead to new and
improved clinical treatment for the relief and prevention of
pathological pain.
Clinical importance of the problem
There are variances in the incidence of CPSP with regard to dif-
ferent operative procedures and different studies. The incidence
of postoperative chronic pain with significant functional deficits
is about 5–10%.17,26.
Mechanisms
Various mechanisms are responsible for the different pain syn-
dromes, even following the same operation. For instance, phan-
tom pain, stump pain and back pain following lower limb
amputations.
CPSP occurs either as a consequence of concurrent inflamma-
tion, or more commonly, as a manifestation of neuropathic pain
caused by surgical injury to peripheral nerves. Inflammatory pain
develops as the result of the release of sensitizing inflammatory
mediators, which lead to a decrease in the threshold of nocicep-
tors innervating the inflammated tissue (peripheral sensitization).
Consequent to an increase in the excitability of neurons in the
central nervous system (central sensitization), inflammatory pain
comes to be associated with exaggerated responses to regular

sensory inputs. Neuropathic pain follows injury to nerves and
the sensory transmission systems in the spinal cord and
the brain.27
In the immediate postoperative period, the clinical picture is
dominated by spontaneous resting and breakthrough pain refer-
ring to the surgical site and its vicinity, which develops through
direct activation of nociceptors, inflammation, and in some cases,
by injury to nerves.27,28
Injury to scalp nerves is inevitable for craniotomy and neuro-
pathic pain may immediately develop and persist in the absence
of any peripheral noxious stimuli or ongoing peripheral inflam-
mation. In clinical practice, CPSP is observed as neuropathic
pain in many patients. In a small group of patients, a continuous
inflammatory response can contribute to maintained inflamma-
tory pain. According to elecent electromyography findings, fol-
lowing thoracotomy, injury of up to 50–100% to the intercostal
nerve conduction around the incision is observed. Moreover, the
degree of nerve damage, which is evaluated by changes in the
sensory threshold and somatosensory evoked responses to elec-
trical stimulation in the thoracotomy scar area, correlates with
the intensity of chronic pain.8
There are clinical studies that contradict these investigations.
Maguire et al. applied electrophysiological tests onto thoracotomy
patients preoperatively, immediately after the operation, and on
the postoperative sixth week and third month, and they could
found no relation between intercostal nerve injury and
chronic pain.
Although the scalp pain importance in the pathophysiological
process of post-surgical pain, it is rarely addressed in the litera-
ture. Because of this, the conclusions about the treatments were
made based on studies that used other types of surgery as a study
method.
Neuronal plasticity and pain
It has been shown in animal and human studies that peripheral
nerve trauma may induce neuroplastic changes in the central
nervous system (central sensitization) causing abnormal sensory
input discharge through the injury site following
wound healing.29
Peripheral nerve injuries lead to neuroimmune interactions.
When an axon is severed, the distal end undergoes degeneration
and engulfment by inflammatory cells. Pain-inducing signal mol-
ecules such as tumor necrosis factor (TNF) are secreted, which
increase the ectopic activity in axons. Microglia, which are cen-
tral macrophage-like cells, are activated to a great extent in the
spinal cord in response to peripheral injury, producing signal
molecules that act on the dorsal horn neurons, which in turn
produce pain hypersensitivity The dorsal horn is the site at which
altered activity and gene expression occur, producing central sen-
sitization, loss of inhibitory interneurons and microglial activa-
tion, resulting in amplification of sensory flow. Descending
controls modulate transmission in the spinal cord. The limibic
system and the hypothalamus play roles in altered mood, behav-
ior and autonomic reflexes. Sensation of pain is generated in the
cortex where past experiences, cultural inputs and expectations
determine all influence the intensity of pain felt. Genotype may
predispose to chronic pain and affect the reaction to treatment.30
Risk factors
Risk factors may be classified as patient-related and treatment
factors. Young women undergoing breast surgery have a weight
BRITISH JOURNAL OF NEUROSURGERY 3
gain and experience more discomfort in the acute postoperative
period and develop CPSP more often than older women. Smith
et al.31 compared the post-mastectomy CPSP in different age
groups and found that the younger age group had a higher inci-
dence of CPSP. Chronic pain was observed in 65% of the 30–49
age group, in 40% of the 50–69 age group, and in 26% of the
over-70 age group. Proobalan et al.32 reported similar rates for
the incidence of chronic pain following hernia operations. In
some clinical studies, postoperative pain is more frequently
observed in women than men.
The importance of other demographic factors such as employ-
ment, housing, and marital status, remains controversial. 31,32
Devor M. hypothesized that certain people are predisposed to
development of pain after nerve injury. Studies in rodents suggest
susceptibility to pain has a strong heritable component, but the
genes responsible remain to be identified. Investigators have sug-
gested that some clinical disorders (fibromyalgia syndrome,
migraine, irritable bowel syndrome, irritable bladder, Raynaud’s
Syndrome) may be markers of post-injury chronic pain.
Opioids
Opioids are good drugs for pain, but may decrease respiratory
function, cause CO2 retention, increasing cerebral blood flow
and intracranial pressure.33,34 Codeine, oxycodone, hydrocodone,
propoxyphene, and morphine are customarily used for postcra-
niotomy pain management.35,36 These drugs stimulate specific
opioid receptors in the central and peripheral nervous system.
The use of narcotics can generate several side effects, possibly
resulting in delayed recovery and ambulation, and extended hos-
pital stays.37
According to Goldsack et al.,38 neurosurgeons resist prescrib-
ing opioids in cases of post-craniotomy pain because of their risk
to cause respiratory depression, decrease level of consciousness,
nausea and vomiting and pupillary effects. Opiates are typically
used on an as-needed basis because of their side effects, in par-
ticular their association with respiratory depression.37
Codeine
It is believed that this substance has its analgesic effect through
agonist activity at mu receptors. The major metabolic pathway of
codeine is the formation of codeine-6-glucuronide. Thus the 0-
demethylation of codeine to morphine by CYP2D6 constitutes a
minor pathway accounting 5–15% of the dose administered.39,40
This medication is widely used in the community because it
carries less risk of respiratory depression, sedation, and miosis
than other opioids.41 However, its effectiveness and safety are
variable. Patients with low CYP2D6 activity do not effectivly con-
vert codeine to morphine; therefore, there is not therapeutic
effect. On the other hand, its hyperactivity leads morphine excess
and can generates toxicity, with risk of respiratory depression
and death 42,43
According to Tanskanen et al.,44 patient controlled analgesia
(PCA) with oxycodone supplemented with either ketoprofen or
paracetamol provides satisfactory postoperative pain relief after
craniotomy and offer a safe option for pain management because
small doses of oxycodone do not cause respiratory depression or
excessive sedation.
Sudheer et al.45 studied 60 craniotomy patients allocated ran-
domly to receive morphine PCA, tramadol PCA or codeine phos-
phate (60mg) intramuscularly. Values of pain score (0–10),
sedation and arterial carbon dioxide tension were recorded at the
4 C. M. T. SANTOS ET AL.
time of first analgesic administration and at 30 min, 1, 4, 8, 12,
18 and 24 h. Morphine use resulted in better analgesia than tra-
madol at all time points and better analgesia than codeine at 4,
12 and 18h. After 24h morphine produced better analgesia and
patient satisfaction than with codeine or tramadol.
In the immediate postoperative period, Gray e Matta46 sup-
port that non-ventilated patients be treated with oral, rectal or
intramuscular codeine phosphate (30–60 mg/4 h) associated with
paracetamol (1 g/6 h) to propitiate a potentiated effect of
the codeine.
Tramadol
This synthetic opiate analgesic is effective without the narcotic
side effects. It also avoids the inhibition of platelets induced by
NSAIDs and some authors consider it underused for the manage-
ment of postoperative pain in neurosurgical patients.37,47,48
Tramadol carries a small risk of seizures in addition to the
high incidence of nausea and vomiting9 which are more common
than with morphine,49,50 codeine51,52 or placebo.53
The analgesic effects of tramadol are related to inhibition of
serotonin and norepinephrine re-uptake, although the exact
mechanism is not known. Tramadol does not alter coagulation
function, but has a weak interaction with opiod receptors which
can lead to nausea, vomiting, dry mouth, and dizziness.47 Use of
tramadol after craniotomy appears to achieve better pain control,
while allowing for the administration of smaller doses of nar-
cotics with paracetamol for pain control.37
After administration of a bolus of 100 mg, this monoaminergic
drug achieves peak effect in 60 min.54,55 However, after an
intravenous injection of nalbuphine its analgesic effect begins in
2–3 min, and its action peak is observed after 30 min.56
A recent study of patients who underwent elective craniotomy
for vascular, tumor and epilepsy procedures blindly randomized
them into two groups. A control group of 25 patients received
narcotics and paracetamol (narcotics group), while 25 patients of
experimental group received tramadol twice daily associated to
narcotic pain medications (tramadol group). The authors con-
cluded that tramadol reduced the length of stay in hospital, visual
analogue scale (VAS) scores, and morphine need, when com-
pared with control group.37
According Verchere,56 after supratentorial craniotomy, remi-
fentanil cannot be managed with paracetamol in rapid infusion
(less than 30 min) or without the addition of an antiemetic
because it increases the incidence of nausea and vomiting.
Addition of tramadol or nalbuphine is necessary to maintain a
good analgesic level (VAS less than 30mm). However, to reach
this objective more rapidly and for a longer period of time is bet-
ter to use nalbuphine.
Morphine
Morphine is well suited to PCA that allows the patient to control
their own analgesia and has been reported as a subjectively better
analgesic provider with overall lower opioid requirement.57 Its
recommended that the total dose in 4h should not exceed 40mg.
Ondansetron is routinely combined with PCA morphine to
achieve higher satisfaction in analgesia and control of nausea
and vomiting.58
In 1996, Goldsack et al.38 compared use of 10mg intramuscu-
lar morphine and 60mg of intramuscular codeine in a double-
blind trial. They demonstrated that morphine was more effective
than codeine in terms of pain relief, fewer doses of morphine
than codeine were required, and none of patients exhibited any
form of respiratory depression, sedation, papillary constriction or
unwanted cardiovascular effects.
Nonsteroidal anti-inflammatory drugs (NSAIDS)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are an option in
post-craniotomy pain management because reduce pain and mor-
phine use by 25–50%54,55 and decrease opioid-induced side
effects.54 The inhibition of prostaglandins caused by these agents
reduces pain and inflammation.59 NSAIDs reduce trombocyte
aggregation, and their use generates risks for postoperative intra-
cranial hematoma34 Paracetamol does not interfere with haemos-
tapostoperative analgesia after craniotomy.60
NSAIDS also inhibit the cyclooxygenase enzyme which has
two distinct isomers: cox-1 and cox-259. Cox-2 blockers are use-
ful in promote analgesia, but cox-1 blockers may lead to platelet
dysfunction and increased bleeding times.
A 100 mg dose of rectal Diclofenac may be used every 18h if
there is a bleeding problem or renal insufficiency.46 However,
administration of NSAIDs after craniotomy is a risk factor for
bleeding.34,61
In 1996, Quiney et al.4 defended use of NSAIDs for control
the post-craniotomy pain. Paracetamol alone has failed to pro-
vide satisfactory analgesia after supratentorial surgery, but when
associated with nalbuphen/tramadol49, and ketoprofen and para-
cetamol with patient-controlled analgesia using oxycodone
proved to be effective.44
Cyclo-Oxygenase 2 inhibitors (COXIBS)
Risk of intracranial bleeding limits use of NSAIDs in neurosur-
gery, but cyclo-oxygenase 2 inhibitors (COXIBs) do not present
the same risk.62–64 These medications are capable of decrease
postoperative craniotomy pain without an increased risk of post-
operative hemorrhage.16 COXIBs are effective in perioperative
analgesics for a variety of surgical procedures and presents mor-
phine-sparring effects from 30% to 50%.65 The limitation for use
this drugs is related to increased risk of cardiovascular disease
due to thromboembolic events.65
A recent paper66 indicated only limited evidence to support
parecoxibe as a postcraniotomy analgesic. The use of these alter-
native analgesics after craniotomy can lead to decrease use of
narcotic medications, can decrease length of hospital stay, and
improve patient satisfaction after a surgical procedure.37
Gabapentin
There is a literature67 suggesting that antiepileptics have antinoci-
ceptive and antihyperalgesic properties. Ture et al.68 verified that
gabapentin (3  400mg), 7 day preoperatively and after surgery,
was successful in relieve acute postoperative pain. Patients who
received gabapentin had a lower anesthetic and analgesic require-
ment during and after craniotomy for supratentorial tumor resec-
tion. However, some collateral effects occurred such as sedation
and delayed extubation. The same study relates that patients who
received gabapentin needed less antiemetic therapy than those
who received phenytoin (3  100mg) as well as reduced opioid
consumption and lower VAS.

Scalp nerve block
Scalp nerve block (SNB) with local anesthetic is an accepted
treatment for postcraniotomy symptoms69 and some authors
hold that it is under-utilized.70 Nguyen et al.16 demonstrate in
their study that a ropivacaine scalp block (20 ml of ropivacaine
0.75%) decreased postoperative pain after craniotomy and infer
from dense C fibers scalp innervation that the main causes of
pain after craniotomy are the skin incision and muscle
disinsertion.
A prospective, randomized, single-blinded, controlled study71
suggests that scalp infiltration in the wound margins with ropiva-
caine (20 ml of ropivacaine 0.75%) has little efficacy against acute
postoperative pain after intracranial tumor resection. This
research suggests that effects of local infiltration are more pro-
nounced in limiting the development of chronic pain states,
regardless of their inflammatory or neuropathic origin.
In a prospective, randomized double-blind study, Biswas and
Bithal72 submitted patients to scalp infiltration with bupivacaine
(25 ml of bupivacaine 0.25%) without adrenaline. Infiltration was
along the proposed line of incision after skin preparation and
before draping to allow 10 min or more to pass prior to incision.
The authors concluded that compared with administration of
intravenous fentanyl at 2mg/kg diluted with normal saline to a
volume of 5 mlg/kg as placebo, 5 min prior to craniotomy, bupi-
vacaine scalp infiltration delayed the onset of demand for add-
itional analgesic. Nevertheless, bupivacaine had no significant
effect on pain when compared to the placebo group.
An investigation on bupivacaine scalp infiltration at 0.25% in
1:200,000 adrenaline73 before incision and after skin closure
found decreased pain on admission to recovery for up to 1 h.
Adrenaline lead to variable vasomotor activity and may add extra
variance to the duration of the effect of local anesthetic given
with it.74
Ayoub et al.24 suppose that morphine at 0.1 mg/kg 1,
administered after dural closure, and a SNB performed with
20 ml of 0.9% saline, administered immediately after surgery,
seem to be equivalent to a SNB with 10 ml of 0.9% saline solu-
tion, after dural closure, and a SNB performed with a 1:1 mixture
of bupivacaine 0.5% and lidocaine 2%, immediately after surgery
for temporary analgesia after remifentanil-based anesthesia.
Chronic postsurgical pain
Chronic postsurgical pain occurs in 33.6% in general anesthesia-
administered cases75. In the same study, a lower frequency of
chronic pain in spinal anesthesia cases as opposed to epidural
anesthesia was explained by the stronger blockade of ‘central
impulse traffic’ in spinal anesthesia. Similarly, in cesarean section
operations compared for spinal and general anesthesia, the inci-
dence of chronic pain was higher in the latter group at the end
of one year76.
Many studies on development of CPSP have been published
about the importance of sufficient treatment of postoperative
pain in the acute period.77–80
The most important dilemmas are probably related to the
medications and methods used. Ketamine is reported to have a
limited acute postoperative analgesic efficacy, and greater long
term effectiveness in antihyperalgesia. It has been suggested that
epidural anesthesia at first is effective in preventing central sensi-
tization during surgery; others disagree.76,81
Some surgical factors appear to be related to pain. Duration
of surgery, surgical technique (laparoscopy versus open), incision
BRITISH JOURNAL OF NEUROSURGERY 5
site and type, experience of the surgeon, and the center where
the intervention is performed have been reported as factors.78,82
Psychosocial factors
Katz et al.83 concluded that preoperative anxiety is a risk factor
in the development of pain for up to 30 days following breast
surgery. The incidence of acute postoperative pain is affected by
catastrophization (exaggerated negative beliefs and response).
Katz et al. studied depression and anxiety in patients with or
without pain following thoracotomy and concluded that pre-
operative assessment may affect the results. In another study on
women undergoing breast cancer surgery, those with increased
preoperative anxiety and depression had a lower degree of anx-
iety but still had a higher degree of pain and depression in the
postoperative first year. Peters et al.84 performed a study on the
somatic and psychosocial predictors of long-term unfavorable
outcomes after surgery. The most significant predictors were the
duration of surgery longer than 3 h and severe acute postopera-
tive pain. Fear of surgery was associated with more pain, poor
recovery and a poor quality of life 6 months post surgery.
According to the study, despite the fact that optimism resulted in
better recovery and a better quality of life, chronic pain and
physical functions were not affected. In a study on 70 lower limb
amputees, psychosocial variables, such as catastrophization, per-
ceived social support and solicitous responding 1 month after the
amputation, predicted phantom pain for up to 3 years following
the amputation.9,76
Shimony et al.85, demonstrate through a prospective, random-
ized and controlled study, using starch as placebo, that
Pregabalin used twice-daily at a dose of 150 mg reduces the pre-
operative anxiety, as well as the postoperative pain score and
analgesic use further improves sleep quality.
New trends
In 2009, research20 indicated that cryotherapy may be useful to
control post-craniotomy pain through application of ice bags on
surgical wound and cold gel packs on periorbital areas, initiating
3 h after surgery, during 3 days, for 20 min per hour. This study
contemplates 97 patients subjected to elective supratentorial cra-
niotomy, separated in cryotherapy and control groups. The level
of pain (VAS score) 3 h after craniotomy was the same to both
groups, but cryotherapy significantly reduced pain 3 days
after surgery.
Perioperative use of twice-daily 150 mg pregabalin attenuates
preoperative anxiety, improves sleep quality, and reduces postop-
erative pain scores and analgesic usage without increasing the
rate of adverse effects. 18,86
The method of surgical approach can function as a prophy-
laxis against postoperative pain. The use of a scalpel for temporal
incision associated with careful repair affected musculature can
prevent tissue damage that leads to acute pain at the sur-
gery site87.
In awake craniotomy procedures, pain may be associated with
the manipulation of skull-base structures or with perivascular
traction. In this case, local scalp block analgesia will not be
effective and the use of opioids will impair brain mapping during
surgery. Thus, as a solution it is possible to change the surgical
approach for transcortical access to the underlying tissues avoid-
ing the traction of the vessels and the base of the skull struc-
tures88. In addition, minimally invasive surgeries associated with
surgical planning based on neuroimaging can reduce surgical
6 C. M. T. SANTOS ET AL.

Figure 1. Protocol to manage post craniotomy acute pain. NSAIDs, non-steroidal anti-inflammatory drugs. Application of ice bags on surgical wound and cold gel
packs on periorbital areas, initiating 3 h after surgery, during 3 days, for 20 min per hour.

damage by allowing smaller scalp incisions, for example, leading ORCID

to a better prognosis of post-surgical pain89.
Nicollas Nunes Rabelo http://orcid.org/0000-0001-5238-8658

Conclusion
Even with conventional pain management, the major part of
patients experience post-craniotomy pain. The use of unusual
approaches, such as scheduled nonopioids, associated to narcotics
may reduce collateral effects related to narcotic medications,
stimulates precocious physical functional recovery, diminish the
period of hospital internment and decline cost during hospital-
ization period.
This study demonstrated that following intraoperative local
intradermal infiltration of the scalp with bupivacaine and lido-
caine combined with postoperative use of dipyrone, patients
reported low levels of pain in the first 12 h after surgery. This
protocol (Figure 1) may contribute not only to the well-being of
patients but also to their hemodynamic stability, which could
possibly permit their early discharge.
It is important that researchers conduct future investigations
focused on ideal protocols for the control of pain after craniot-
omy because this would make it possible to offer an improved
and individualized pain management plan to this special group
of patients.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
1. Basbaum AI. Spinal mechanisms of acute and persistent pain. Reg
Anesth Pain Med 1999;24:59–67.
2. Raja SN, Dougherty PM. Reversing tissue injury-induced plastic
changes in the spinal cord: the search for the magic bullet. Reg Anesth
Pain Med 2000;25:441–4.
3. De Benedittis G, Lorenzetti A, Migliore M, Spagnoli D, Tiberio F,
Villani RM. Postoperative pain in neurosurgery: a pilot study in brain
surgery. Neurosurgery 1996;38:466–9. discussion 469–470
4. Quiney N, Cooper R, Stoneham M, Walters F. Pain after craniotomy.
A time for reappraisal? Br J Neurosurg 1996;10:295–9.
5. Gee JR, Ishaq Y, Vijayan N. Postcraniotomy headache. Headache 2003;
43:276–8.
6. Irefin SA, Schubert A, Bloomfield EL, DeBoer GE, Mascha EJ,
Ebrahim ZY. The effect of craniotomy location on postoperative pain
and nausea. J Anesth 2003;17:227–31.
7. Mordhorst C, Latz B, Kerz T, et al. Prospective assessment of postop-
erative pain after craniotomy. J Neurosurg Anesthesiol 2010;22:202–6..
8. Roberts GC. Post-craniotomy analgesia: current practices in British
neurosurgical centres – a survey of post-craniotomy analgesic practices.
Eur J Anaesthesiol 2005;22:328–32.
9. Talke PO, Gelb AW. Postcraniotomy pain remains a real headache.
Eur J Anaesthesiol 2005;22:325–7.
10. Rawal N. Acute pain services revisited–good from far, far from good?
Reg Anesth Pain Med 2002;27:117–21.
11. Agency for Health Care Policy and Research, Public Health Service, US
Department of Health and Human Services. Acute Pain Management
Guideline Panel: acute pain management: operative or medical

procedures and trauma. Clinical practice guidelines. AHCPR
Publication No. 92–0032. Rockville (MD): US Public Health Service;
1992.
12. Agency for Health Care Policy and Research. Cancer pain guidelines:
clinical practice guideline: management of cancer pain. AHCPR
Publication No. 94–0592. Rockville (MD): US Public Health Service;
1994.
13. American Pain Society Quality of Care Committee. Quality improve-
ment guidelines for the treatment of acute pain and cancer pain.
JAMA 1995;274:1874–80.
14. Bardiau FM, Taviaux NF, Albert A, Boogaerts JG, Stadler M. An inter-
vention study to enhance postoperative pain management. Anesth
Analg 2003;96:179–85.
15. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during
remifentanil infusion in humans. Anesth Analg 1998;86:1307–11.
16. Nguyen A, Girard F, Boudreault D, et al. Scalp nerve blocks decrease
the severity of pain after craniotomy. Anesth Analg 2001;93:1272–6.
17. Gray’s Anatomy. The anatomical basis of clinical practice. 39th ed.
Edinburgh (UK): Churchill Livingstone; 1995.
18. Buvanendran A, Kroin JS, Kari M, Tuman KJ. Can a single dose of
300 mg of pregabalin reach acute antihyperalgesic levels in the central
nervous system? Reg Anesth Pain Med 2010;35:535–8.
19. Blanshard HJ, Chung F, Manninen PH, Taylor MD, Bernstein M.
Awake craniotomy for removal of intracranial tumor: considerations
for early discharge. Anesth Analg 2001;92:89–94.
20. Shin YS, Lim NY, Yun SC, Park KO. A randomised controlled trial of
the effects of cryotherapy on pain, eyelid oedema and facial ecchymosis
after craniotomy. J Clin Nurs 2009;18:3029–36.
21. Notermans SLH, Tophoff MMWA. Sex difference in pain tolerance
and pain apperception. Psychiatr Neurol Neurochir 1967;70:23–29.
22. Woodrow KM, Friedman GD, Siegelaub AB, Collen MF. Pain toler-
ance: differences according to age, sex and race. Psychosom Med 1972;
34:548–56.
23. Ferreira KS, Dach F, Speciali JG. Scar neuromas as triggers for head-
ache after craniotomy: clinical evidence. Arq Neuro-Psiquiatr 2012;70:
206–9.
24. Pfund Z, Szapary L, Jaszberenyi O, Nagy F, Czopf J. Headache in intra-
cranial tumors. Cephalalgia 1999;19:787–90. discussion 765
25. Rabelo NN, Rabelo NN, Machado FS, et al. Critical Analysis of
Sedation and Analgesia in Severe Head. TraumaArq Bras Neurocir
2016;35:135–47.
26. Sansone P, Pace MC, Passavanti MB, Pota V, Colella U, Aurilio C,
Epidemiology and Incidence of Acute and Chronic Post-Surgical Pain.
Ann Ital Chir 2015;86:285–92.
27. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk fac-
tors and prevention. Lancet 2006;367:1618–25.
28. Smith DG, Ehde DM, Legro MW, Reiber GE, del Aguila M, Boone
DA. Phantom limb, residual limb, and back pain after lower extremity
amputations. Clin Orthop Relat Res 1999;361:29–38.
29. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain.
Science 2000;288:1765–9.
30. Jensen TS, Baron R. Translation of symptoms and signs into mecha-
nisms in neuropathic pain. Pain 2003;102:2–18.
31. Smith WC, Bourne D, Squair J, Phillips DO, Chambers WA. A retro-
spective cohort study of post mastectomy pain syndrome. Pain 1999;
83:91–5.
32. Poobalan AS, Bruce J, King PM, Chambers WA, Krukowski ZH, Smith
WC. Chronic pain and quality of life following open inguinal hernia
repair. Br J Surg 2001;88:1122–6.
33. Cold GE, Felding M. Even small doses of morphine might provoke
“luxury perfusion” in the postoperative period after craniotomy [letter].
Neurosurgery 1993;32:327.
34. Palmer JD, Sparrow OC, Iannotti F. Postoperative hematoma: a 5-year
survey and identification of avoidable risk factors. Neurosurgery 1994;
35:1061–4. discussion 1064–1065
35. Herbert C. Use of morphine for pain after intracranial surgery. Prof
Nurse 2001;16:1029–33.
36. Stoneham MD, Cooper R, Quiney NF, Walters FJ. Pain following cra-
niotomy: a preliminary study comparing PCA morphine with intra-
muscular codeine phosphate. Anaesthesia 1996;51:1176–8.
37. Rahimi SY, Alleyne CH Jr, Vernier E, Witcher MR, Vender JR.
Postoperative pain management with tramadol after craniotomy: evalu-
ation and cost analysis. J Neurosurg 2010;112:268–72.
38. Goldsack C, Scuplak SM, Smith M. A double-blind comparison of
codeine and morphine for postoperative analgesia following intracra-
nial surgery. Anaesthesia 1996;51:1029–32.
BRITISH JOURNAL OF NEUROSURGERY 7
39. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and
metabolism of codeine after single and chronic doses in one poor and
seven extensive metabolisers. Br J Clin Pharmacol 1991;31:381–90.
40. Yue QY, Hasselstr€ om J, Svensson JO, S€awe J. Pharmacokinetics of
codeine and its metabolites in Caucasian healthy volunteers: compari-
sons between extensive and poor hydroxylators of debrisoquine. Br J
Clin Pharmacol 1991;31:635–42.
41. Cousins MJ, Umedaly HS. Postoperative pain management in the
neurosurgical patient. Int Anesthesiol Clin 1996;34:179–93.
42. Ramsey LB, Brown JT, Vear SI, Bishop JR, Van Driest SL. Annual
review of pharmacology and toxicology gene-based dose optimization
in children. Annu Rev Pharmacol Toxicol 2020;60:311–21.
43. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine
metabolism in an urban population of children and its implications for
analgesic reliability. Br J Anaesth 2002;89:839–45.
44. Tanskanen P, Kytt€a J, Randell T. Patient-controlled analgesia with oxy-
codone in the treatment of postcraniotomy pain. Acta Anaesthesiol
Scand 1999;43:42–5.
45. Sudheer PS, Logan SW, Terblanche C, Ateleanu B, Hall JE.
Comparison of the analgesic efficacy and respiratory effects of mor-
phine, tramadol and codeine after craniotomy. Anaesthesia 2007;62:
555–60.
46. de Gray LC, Matta BF. Acute and chronic pain following craniotomy:
a review. Anaesthesia 2005;60:693–704.
47. Leppert W, Łuczak J. The role of tramadol in cancer pain treatment –
a review. Support Care Cancer 2005;13:5–17.
48. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol.
JAMA 1997;278:1661.
49. Ng KF, Tsui SL, Yang JC, Ho ET. Increased nausea and dizziness
when using tramadol for post-operative patient-controlled analgesia
(PCA) compared with morphine after intraoperative loading with mor-
phine. Eur J Anaesthesiol 1998;15:565–70.
50. Pang WW, Mok MS, Lin CH, Yang TF, Huang MH. Comparison of
patient-controlled analgesia (PCA) with tramadol or morphine. Can J
Anesth/J Can Anesth 1999;46:1030–5.
51. Jeffrey HM, Charlton P, Mellor DJ, Moss E, Vucevic M. Analgesia after
intracranial surgery: a double-blind, prospective comparison of codeine
and tramadol. Br J Anaesth 1999;83:245–9.
52. Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effect of 50 and
100 mg oral tramadol after orthopaedic surgery: a randomized, double-
blind, placebo and standard active drug comparison. Pain 1995;62:
111–8.
53. Stamer UM, Maier C, Grond S, Veh-Schmidt B, Klaschik E, Lehmann
KA. Tramadol in the management of post-operative pain: a double-
blind, placebo- and active drug-controlled study. Eur J Anaesthesiol
1997;14:646–54.
54. Schug SA, Manopas A. Update on the role of non-opioids for postop-
erative pain treatment. Best Pract Res Clin Anaesthesiol 2007;21:15–30.
55. Gan TJ, Joshi GP, Zhao SZ, Hanna DB, Cheung RY, Chen C.
Presurgical intravenous parecoxib sodium and follow-up oral valde-
coxib for pain management after laparoscopic cholecystectomy surgery
reduces opioid requirements and opioid-related adverse effects. Acta
Anaesthesiol Scand 2004;48:1194–207.
56. Verchere E, Grenier B, Mesli A, Siao D, Sesay M, Maurette P.
Postoperative pain management after supratentorial craniotomy. J
Neurosurg Anesthesiol 2002;14:96–101.
57. Jellish WS, Murdoch J, Leonetti JP. Perioperative management of com-
plex skull base surgery: the anesthesiologist’s point of view. FOC 2002;
12:e5.
58. Jellish WS, Leonetti JP, Kristina S, Douglas A, Origitano TC.
Morphine/ondansetron PCA for postoperative pain, nausea and vomit-
ing after skull base surgery. Otolaryngol Head Neck Surg 2006;135:
175–81.
59. Ferreira SH, Moncada S, Vane JR. Prostaglandins and the mechanism
of analgesia produced by aspirin-like drugs. Br J Pharmacol 1973;49:
86–97.
60. Stoneham MD, Walters FJM. Post-operative analgesia for craniotomy
patients: current attitudes among neuroanaesthetists. Eur J Anaesthesiol
1995;12:571–5.
61. Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale
for use in severe postoperative pain. Br J Anaesth 1991;66:703–12.
62. Hegi TR, Bombeli T, Seifert B, et al. Effect of rofecoxib on platelet
aggregation and blood loss in gynaecological and breast surgery com-
pared with diclofenac. Br J Anaesth 2004;92:523–31.
63. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects
of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in
8 C. M. T. SANTOS ET AL.
healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000;
40:124–32.
64. Leese PT, Recker DP, Kent JD. The COX-2 selective inhibitor, valde-
coxib, does not impair platelet function in the elderly: results of a
randomized controlled trial. J Clin Pharmacol 2003;43:504–13.
65. Schug SA, Joshi GP, Camu F, et al. Cardiovascular safety of the cyclo-
oxygenase-2 selective inhibitors parecoxib and valdecoxib in the post-
operative setting: an analysis of integrated data. Anesth Analg 2009;108:
299–307.
66. Jones SJ, Cormack J, Murphy MA, Scott DA. Parecoxib for analgesia
after craniotomy. Br J Anaesth 2009;102:76–9.
67. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain
management. Anaesthesia 2002;57:451–62.
68. T€ure H, Sayin M, Karlikaya G, Bingol CA, Aykac B, T€ ure U. The anal-
gesic effect of gabapentin as a prophylactic anticonvulsant drug on
postcraniotomy pain: a prospective randomized study. Anesth Analg
2009;109:1625–31.
69. Hartley EJ, Bissonnette B, St-Louis P, Rybczynski J, McLeod ME. Scalp
infiltration with bupivacaine in pediatric brain surgery. Anesth Analg
1991;73:29–32.
70. Bala I, Gupta B, Bhardwaj N, Ghai B, Khosla VK. Effect of scalp block
on postoperative pain relief in craniotomy patients. Anaesth Intensive
Care 2006;34:224–7.
71. Batoz H, Verdonck O, Pellerin C, Roux G, Maurette P. The analgesic
properties of scalp infiltrations with ropivacaine after intracranial
tumoral resection. Anesth Analg 2009;109:240–4.
72. Biswas BK, Bithal PK. Preincision 0.25% bupivacaine scalp infiltration
and postcraniotomy pain: a randomized double-blind, placebo-con-
trolled study. J Neurosurg Anesthesiol 2003;15:234–9.
73. Bloomfield EL, Schubert A, Secic M, Barnett G, Shutway F, Ebrahim
ZY. The influence of scalp infiltration with bupivacaine on hemo-
dynamics and postoperative pain in adult patients undergoing craniot-
omy. Anesth Analg 1998;87:579–82.
74. Aps C, Reynolds F. The effect of concentration on vasoactivity of bupi-
vacaine and lignocaine. Br J Anaesth 1976;48:1171–4.
75. €
Akkaya T, Ozkan D. Chronic post-surgical pain. Agri 2009;21:1–9.
76. Wright D, Paterson C, Scott N, Hair A, O’Dwyer PJ. Five-year follow-
up of patients undergoing laparoscopic or open groin hernia repair: a
randomized controlled trial. Ann Surg 2002;235:333–7.
77. Devor M. Evidence for heritability of pain in patients with traumatic
neuropathy. Pain 2004;108:200–1.
78. Mogil JS, Wilson SG, Bon K, et al. Heritability of nociception I:
responses of 11 inbred mouse strains on 12 measures of nociception.
Pain 1999;80:67–82.
79. Mogil JS, Yu L, Basbaum AI. Pain genes?: natural variation and trans-
genic mutants. Annu Rev Neurosci 2000;23:777–811.
80. Courtney CA, Duffy K, Serpell MG, O’Dwyer PJ. Outcome of patients
with severe chronic pain following repair of groin hernia. Br J Surg
2002;89:1310–4.
81. Katz J, Cohen L. Preventive analgesia is associated with reduced pain
disability 3 weeks but not 6 months after major gynecologic surgery by
laparotomy. Anesthesiology 2004;101:169–74.
82. Hartvigsen J, Christensen K, Frederiksen H, Petersen HC. Genetic and
environmental contributions to back pain in old age: a study of 2,108
Danish twins aged 70 and older. Spine (Phila Pa 1976) 2004;29:
897–901. discussion 902
83. Majumdar JR, Vertosick EA, Cohen B, Assel M, Levine M, Barton-
Burke M. Preoperative anxiety in patients undergoing outpatient can-
cer surgery. Asia Pac J Oncol Nurs 2019;6:440–5.
84. Peters ML, Sommer M, de Rijke JM., et al. Somatic and psychologic
predictors of long-term unfavorable outcome after surgical interven-
tion. Ann Surg 2007;245:487–94.
85. Shimony N, Amit U, Minz B, et al. Perioperative pregabalin for reduc-
ing pain, analgesic consumption, and anxiety and enhancing sleep
quality in elective neurosurgical patients: a prospective, randomized,
double-blind, and controlled clinical study. JNS 2016;125:1513–22.
86. Burke SM. Shorten GD: Perioperative pregabalin improves pain and
functional outcomes 3 months after lumbar discectomy. Anesth Analg
2010;110:1180–5.
87. Lutman B, Bloom J, Nussenblatt B, Romo V. A contemporary perspec-
tive on the management of post-craniotomy headache and pain. Curr
Pain Headache Rep 2018;22:1–7.
88. Kulikov A, Lubnin A. Anesthesia for awake craniotomy. Current
Opinion in Anaesthesiology 2018;31:1–5.
89. Thomas DGT, Kitchen ND. Minimally invasive surgery. BMJ 1994;308:
126–8.