In recent years, the focus on the challenges in treatment of postoperative pain following craniotomy has increased. Several studies have assessed postoperative pain following craniotomy and found it to be disturbingly high.1–7 In a recent study by Mordhorst et al.,2 up to 55% of patients had moderate or severe postoperative pain in the first 24 h following craniotomy. That study confirmed the results of the pilot study by De Benedittis et al.3 in which 60% of patients experienced postoperative pain. In contrast to these results, a large retrospective study demonstrated that patients undergoing intracranial surgery had limited analgesic requirements and low pain scores.8 However, the anaesthetic technique used during surgery was opioid-based, and as the results were attained only in the postanaesthesia care unit (PACU), where the patients spent an average time of 90 min, the use of intraoperative opioids is likely to have influenced early postoperative pain scores. Furthermore, several studies between 1996 and 2009 have reported results confirming the belief that postoperative pain following craniotomy is a persistent concern, and that new analgesic strategies are needed.4–7,9,10
An optimal analgesic therapy is of great importance because suboptimal analgesic therapy causes discomfort to the patient and may lead to an increase in the incidence of postoperative complications and hence to a prolonged hospital stay and an increase in health expenses.11
Nemergut et al.1 reviewed the literature on pain management after craniotomy in 2007 and demonstrated that the data available at that time did not permit construction of a therapeutic guideline on postcraniotomy pain. However, new trials have been conducted since 200712–28 and a systematic update with thorough methodology is needed.
The aim of this systematic review is, therefore, to evaluate the current evidence on analgesic therapy following craniotomy.
Reports of randomised controlled trials (RCTs) pertinent to postoperative pain relief after craniotomy were systematically sought using the PubMed database, Embase, Cochrane library, Google scholar and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) without language restriction. Free text combinations including the following search terms were used: craniotomy, postoperative pain, pain, analgesia, local anaesthetic, bupivacaine, ropivacaine, levobupivacaine, non-steroidal anti-inflammatory drug (NSAID), opioid and codeine. Reference lists from retrieved articles were searched for additional papers. The last search was performed on 15 December 2010.
Reports were considered for inclusion if they were RCTs, reported to be double-blind, of any analgesic or analgesic method for postoperative pain relief compared with placebo in adult patients (>18 years) undergoing craniotomy. Only studies with pain or supplemental postoperative analgesic consumption as an endpoint were included in the final analysis. Clinicaltrials.gov, controlled-trials.com and who.int/trialsearch were screened for any ongoing but unpublished studies. All sites were last visited 20 December 2010.
We required full journal publication or summary clinical trial reports in English for inclusion. Brief abstracts and letters were excluded.
Each of the reports was read by two of the authors (M.S.H. and J.B.D.) and quality-assessed using a three-item instrument on a 0–5 quality scale.29 The studies were given one point if they were described as randomised and were given one additional point if the method of randomisation was described and appropriate (e.g. computer generated). One point was given if the study was described as double-blind, and one additional point was given if the method of blinding was described and appropriate (e.g. identical placebo). Finally, one point was given if withdrawals or dropouts were described. One point was deducted if the randomisation was inadequate, and another point if the blinding was inadequate.
Trials were assessed for risks of bias in a three-item methodological quality table incorporating randomisation, allocation concealment and double-blinding30 (Table 1).14–17,31–35 If a trial was described as randomised, and the method was described and considered appropriate, it received a green mark; if the description of the randomisation was inadequate, it received a yellow mark; and if the trial was not randomised, it received a red mark.36 Similar assessments were made for the two remaining items. Cochrane criteria for judging risk of bias in the three items were followed.37
Data from the studies were extracted onto a datasheet (M.S.H.) (Table 2).14–17,31–35 These included surgical procedure; number of patients in the intervention and control groups; anaesthetic; basic analgesic regimen; type and time of administration of pain treatment; pain scores; type and amount of, and effect on, supplemental analgesic requirements; and possible side-effects (nausea, vomiting, dizziness and sedation). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed.38 Qualitative analysis of postoperative efficacy was evaluated by assessment of significant difference (P < 0.05 as reported in the original paper) in pain relief and consumption of supplemental analgesics between study groups.
We planned to perform quantitative analyses of combined data by calculation of weighted mean differences (WMDs) of pain scores (primary endpoint), and of WMD of cumulative use of supplemental analgesics between study groups, whenever sufficient data were provided in the original papers [e.g. standard deviation (SD), number of included patients in each study group and the relevant mean value].
The search yielded 36 RCTs of postoperative analgesic therapy after craniotomy, and three ongoing and unpublished trials. Only nine of the 36 RCTs met the inclusion criteria and only these studies were included in the final analysis (Fig. 1). Reasons for exclusion were primarily lack of placebo control (Table 3).9,12,13,18–28,39–51 The included studies did not present a sufficiently homogeneous group of trials to allow meta-analysis. Consequently, only a qualitative analysis was performed.
As shown in Table 2, we divided the nine studies into three groups according to the type of analgesia: scalp infiltration, scalp block and other analgesic methods.
Five RCTs of wound infiltration vs. placebo were identified.14–16,31,32 They included a total of 249 patients of whom 112 received infiltration with local anaesthetic vs. 137 controls. The studies were generally of reasonable quality with an Oxford quality score ranging from 3 to 5 (Table 2). The methodological quality assessment demonstrated that one study31 had an inadequate description of randomisation, and three studies14–16 had inadequate allocation concealment (Table 1). The perioperative anaesthetic used was either inhalational anaesthesia or total intravenous anaesthesia (TIVA). Postoperative pain was the primary outcome in four studies,14–16,32 and in one study,31 it was registered as a secondary outcome. One study31 described infiltration at the skull pin sites as well as at the incision site, and one study16 investigated only the effect of skull pin site infiltration. Three studies15,16,31 investigated the effect of bupivacaine, one study32 examined the effects of ropivacaine and bupivacaine and one study14 examined the effect of ropivacaine. None of the studies specified whether pain was evaluated at rest or on mobilisation.
A significant reduction in visual analogue scale (VAS) scores immediately on admission to the PACU following injection of bupivacaine was demonstrated in one study,31 but no significant differences were found 1 h postoperatively. Another study15 reported a significantly reduced verbal numerical scale (VNS) score after 1 h, but no significant differences in the following 12 h postoperatively. In the study by Law-Koune et al.,32 which compared infiltration with bupivacaine, ropivacaine and placebo before final closure of the scalp, no significant differences in VAS pain scores were demonstrated among the groups, but morphine consumption in the first 2 h was reduced in the active treatment groups compared to the placebo group. However, the cumulative amount of morphine administered 16 h postoperatively was similar in all three groups. El-Dawlatly et al.16 demonstrated that infiltration of the skull pin sites with bupivacaine significantly reduced VAS pain scores at 2, 4, 36 and 48 h postoperatively.
Infiltration with ropivacaine significantly reduced the VAS pain score at 0–24 h postoperatively, but had no significant effect on postoperative analgesic requirements.14 No major side-effects were reported in any of the studies of scalp infiltration.
Scalp nerve block
Two RCTs of nerve scalp block vs. placebo were identified33,34 with a total of 70 patients of whom 35 received scalp block with a local anaesthetic. The studies obtained a quality score of 2 and 4, respectively. One study33 had no adequate description of randomisation or double blinding and no adequate allocation concealment, and one study34 had no adequate description of allocation concealment (Table 1). Inhalational anaesthesia was used as the general anaesthetic in both studies, and the scalp block was performed as described by Pinosky et al.52 Both studies had postoperative pain as the primary outcome. Neither of the studies specified whether pain was evaluated at rest or on mobilisation. One study33 investigated the effect of scalp block with ropivacaine and demonstrated a significant reduction in VAS pain scores at 4, 12 and 24 h postoperatively, but no significant difference in postoperative analgesic requirements. In the other study with bupivacaine, Bala et al.34 demonstrated a reduction in VNS pain scores at 0–6 h postoperatively, a significant reduction in postoperative analgesic requirements and a prolonged time before the need for rescue analgesics.
Two RCTs of patient-controlled analgesia (PCA) with morphine vs. placebo35 and the cyclo-oxygenase type 2 (COX- 2) inhibitor parecoxib vs. placebo17 were identified. Both studies were of reasonable quality with quality scores of 4 and 5, respectively, and both studies had postoperative pain as the primary outcome. Methodological quality assessment demonstrated that both studies had a low risk of bias (Table 1). However, neither study specified whether pain was evaluated at rest or on mobilisation. PCA morphine caused a reduction in the total analgesic rescue dose in the 24-h study period from 7.9 to 4.9 mg.35 However, no significant differences in total morphine consumption were demonstrated between the groups. Jones et al.17 investigated the effect of parecoxib 24 h postoperatively and reported a reduction in pain scores 6 h postoperatively and a reduction in postoperative morphine consumption 12 h postoperatively.
Three ongoing and unpublished trials were identified. One was investigating the effect of parecoxib,53 one the effect of scalp nerve block54 and one the effect of intravenous PCA.55
During the past few years, many experts have expressed concerns that postcraniotomy pain seems to be underestimated and inadequately managed.1,10,56–58 Nemergut et al.1 concluded that evidence about postcraniotomy pain management was very limited. There was a lack of large trials investigating pain, and no trials examined intraoperative anaesthetic regimens. Since they conducted their review, 16 new RCTs have been performed,12,14–28 although only four met our inclusion criteria (Tables 2 and 3).
Several observational studies have estimated that pain following craniotomy is moderate to severe during the first 24–48 h.2–7 Because postcraniotomy pain is believed to be superficial, located at the area of incision, and have a somatic and pericranial muscular origin,3,4,59 infiltration of the scalp seems logically to be a good analgesic option in the immediate postoperative period. The studies of this technique that we analysed demonstrate that scalp infiltration with bupivacaine or ropivacaine has a significant analgesic effect in the first few postoperative hours.14–16,31,32 Furthermore, two of the five studies15,16 demonstrated a significant analgesic effect that extended up to 24 and 48 h. The reason for the varied duration of action of scalp infiltration is unknown, but some limitations in the studies that we analysed might account for the differences.
An important limitation of the study by Bloomfield et al.31 is that pain was assessed only at 1 h postoperatively. Therefore, any possible differences in pain between the two groups during the later postoperative period remain unknown. Furthermore, patients with supratentorial tumours were given intravenous dexamethasone 10 mg intraoperatively, which may have had an effect on postoperative pain.60 However, as the distribution of patients with supratentorial tumours in the bupivacaine group and the control group is not indicated, we cannot determine whether the intraoperative dexamethasone could have affected the postoperative pain scores. El-Dawlatly et al.16 demonstrated that infiltration of skull pin sites with bupivacaine in combination with a basic analgesic regimen with tenoxicam reduced pain for up to 48 h postoperatively. However, the durations of the analgesic effect in other studies performed with bupivacaine15,31,32 contradict these findings. Batoz et al.14 infiltrated the scalp with ropivacaine and demonstrated a significant analgesic effect 24 h postoperatively. In comparison with the study performed by Law-Koune et al.,32 in which no significant changes in VAS pain scores were recorded, the anaesthetic technique in the two studies differed (TIVA vs. inhalational anaesthesia). Mordhorst et al.2 demonstrated that pain intensity was higher when using sevoflurane compared to TIVA, but more studies are needed to confirm whether the anaesthetic technique is accountable for the differences in the duration of analgesia.
In summary, scalp infiltration seems to provide good analgesia in the first few postoperative hours, but the reported durations of action are variable and more studies are needed.
The two studies of scalp nerve block33,34 both reported an effect that lasted for 4–6 h postoperatively. However, a comparison of the two studies is problematic. First, Nguyen et al.33 investigated the effect of ropivacaine, whereas Bala et al.34 investigated the effect of bupivacaine. It is remarkable that ropivacaine, a drug with a shorter duration of action than bupivacaine, had a longer-lasting analgesic effect. Nguyen et al.33 suggested that this might result from a preemptive analgesic effect, although that is debatable. More studies are needed to clarify the duration of effect of scalp nerve block. Second, Nguyen et al.33 recorded the first VAS pain scores 4 h postoperatively and their study does not address immediate postoperative analgesic effects. Bala et al.34 recorded VAS pain scores from 0 to 12 h postoperatively and consequently, this study does not provide evidence for an analgesic effect beyond the 12-h period.
In spite of the differences, it seems that postoperative analgesia provided by scalp nerve block is longer lasting and superior to the analgesia provided by scalp infiltration, but the use of scalp nerve block requires more effort, skill and time compared to scalp infiltration. Furthermore, no studies comparing the two methods have been published.
Only two RCTs investigating other treatment modalities were encountered.17,35 COX-2 inhibitors, with no antiplatelet action and no increased bleeding risk, seem to be ideal for postcraniotomy pain. However, Jones et al.17 found only limited evidence to support the use of parecoxib in postcraniotomy analgesia. Conversely, in an excluded study by Doménech et al.,28 it was reported that intravenous parecoxib 40 mg resulted in significantly lower pain scores compared to placebo. The introduction of COX-2 inhibitors is interesting and requires more studies for further evaluation.
The use of morphine in postcraniotomy patients is debatable. In the only identified placebo-controlled RCT, Jellish et al.35 found that PCA with morphine had a good analgesic effect with no significant incidences of nausea or other side-effects. Other excluded studies25,39 have investigated PCA with morphine and found it to be an acceptable option for postcraniotomy pain. In other excluded trials, the use of other analgesics, such as codeine phosphate,40 tramadol41 and nalbuphine42 have been studied, with variable results.
The general fear of using opioids because of respiratory depression and sedation, and the fact that they may mask neurological assessment, have led to the wide use of codeine phosphate as a first-line analgesic after neurosurgical procedures, as codeine phosphate was believed to have minimal respiratory depressant effect, and not to mask pupillary signs.61 However, only 5–10% of the CYP450-dependent drug is metabolised in the liver to its active compound morphine. Furthermore, it is estimated that 7–10% of the European population are poor metabolisers,62 in whom codeine phosphate has a very limited analgesic effect. A recent systematic review of single-dose oral codeine 60 mg demonstrated a number needed to treat (NNT) of 12 for at least 50% pain relief over 4–6 h.63 In comparison with ibuprofen 400 mg64 and paracetamol 1 g,65 with NNTs of 2.5 and 3.6, respectively, codeine appears to be inferior. The limited analgesic effect of codeine phosphate is well known, and it has been found by many to be inadequate in the management of all postcraniotomy pain.66 However, a procedure-specific approach to the use of codeine-phosphate is necessary to adequately assess the efficacy of codeine phosphate pertinent to post-craniotomy pain relief.
Gabapentin has proved to have valuable analgesic effects after a variety of surgical procedures,67–69 but its use in the treatment of postcraniotomy pain is still unclear. In an excluded study, Türe et al.19 reported a beneficial analgesic effect of gabapentin compared to phenytoin, with a concomitant reduction in postoperative analgesic consumption. It did, however, increase the sedation scores for the first 2 h after operation. The introduction of gabapentinoids in the neurosurgical field is interesting, and further studies are required to reveal whether these substances have a place in postcraniotomy analgesia.
Similarly, the role of NSAIDs in management of pain after craniotomy is unclear. Dolmatova et al.23 investigated the effect of scheduled lornoxicam in 126 craniotomy patients and found no postoperative haematomas or renal failure in their study population. However, the small size of the study does not provide adequate reassurance about the use of NSAIDs in postcraniotomy patients, and the potential risks associated with the short-term use of NSAIDs have to be considered. The antiplatelet effect of NSAIDs may increase the risk of postoperative haematoma.70 It has been argued that NSAIDs should be stopped prior to intracranial surgery,71 and more evidence is required to determine the safety and efficacy of NSAIDs for postcraniotomy analgesia.
In addition to pain, postoperative nausea and vomiting (PONV) is a major concern after craniotomy. PONV is a serious complication which can lead to a potential elevation of intracranial pressure and a risk of haemorrhage. Steroids have a well known effect on PONV, and in a recent observational study, it was demonstrated that the use of intraoperative steroids reduced the risk of postcraniotomy pain.2 The use of steroids which may have both analgesic and antiemetic effects could be of interest in the treatment of postcraniotomy pain and PONV.
Multimodal analgesia may be an optimal solution to postcraniotomy pain and opioid-induced PONV. The use of a combination of various analgesic drug classes with different mechanisms of action and side-effect profiles might result in additive or synergistic analgesic effects, reducing opioid consumption, possibly reducing side-effects and consequently improving outcome.72,73 It is also important to be aware that different surgical procedures may result in different pain characteristics, and that the efficacy of analgesic agents may vary among neurosurgical procedures.74 Present evidence is a product of pooled data from an array of different surgical procedures and in order to optimise analgesic therapy pertinent to postcraniotomy pain, studies of procedure-specific outcomes are required.
Evidence for the use of otherwise common analgesics after craniotomy is very limited, and a future research agenda should include RCTs of the analgesic and opioid-sparing effects of paracetamol, NSAIDs, COX-2 inhibitors, gabapentin and other analgesic adjuvants, alone and in combination, on pain after various intracranial surgical procedures. Systematic trials investigating the possible analgesic effects of pre- and intraoperative steroids would be of particular interest. RCTs of scalp infiltration and/or nerve block with a larger number of patients and an estimate of the exact duration of action are needed. In order to quantify the different pain characteristics and surgical approaches of the various types of craniotomy, analgesic treatment should be investigated in procedure-specific trials, and possible high pain responders such as younger patients should be studied.2,3,5,7 Pain should be evaluated in both the resting and the active/mobilising patient (e.g. walking). Finally, time to return of motor and sensory skills, time to discharge and overall medical costs could be potential areas for investigation in such studies.
Our study has some limitations. We did not translate the retrieved articles into English and did not contact authors regarding trial protocols and full trial information. In addition, we did not contact the authors for retrieval of full articles of the identified abstracts.13,47
In conclusion, firm recommendation on analgesic therapy following craniotomy is not possible due to the fact that the number of well performed RCTs is limited, and the study populations are too small. The identification of 16 new trials since 2007 seems encouraging, but as only four RCTs met our inclusion criteria, the base of evidence remains small. Consequently, we are in urgent need of systematic and procedure-specific studies in this field of research.
The work was not funded and had no financial support or sponsorship.
None of the authors has any conflict of interest.
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